Blinatumomab for the treatment of acute lymphoblastic leukemia

Kaplan, Jason; Grischenko, Marina; Giles, Francis J.

doi:10.1007/s10637-015-0289-4

Cited by 27 publications

(23 citation statements)

References 49 publications

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“…Early clinical experience with blinatumumab showed significant toxicities related to cytokine release syndrome (CRS) and generalized immune activation that were mitigated by incorporating an initial stepwise increase in dose level. 13 We were able to circumvent toxicities related to CRS by using a low-affinity CD3 arm and identifying a dose level that provided acceptable safety while maintaining robust activity. Finally, CLL1/CD3L TDB was otherwise well tolerated without clinical or histopathologic signs of neurotoxicity, an adverse event that has been reported for CD19 T-cell therapies, including blinatumumab.…”

Section: Discussionmentioning

confidence: 99%

“…This necessitates constant infusion to maintain exposure. 13 A full-length human IgG1 bispecific antibody engineered for improved PK and altered Fc-mediated functions could address many of these shortfalls.…”

Section: /Cd38mentioning

confidence: 99%

“…Finally, we investigated whether the GEMM could be used to monitor target cell depletion beyond the normal recovery period of blood cells (days [10][11][12][13][14]. Sca1…”

Section: Cd8mentioning

confidence: 99%

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An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

Leong¹,

Sukumaran²,

Hristopoulos³

et al. 2017

Blood

137

128

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• Bispecific antibodies binding CD3 and CLL-1 deplete CLL-1 1 target cells in animal models.• An appropriately engineered CLL-1/CD3 bispecific antibody could be effective in treating AML.Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML. CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery. We selected a high-affinity monkey cross-reactive anti-CLL-1 arm and tested several anti-CD3 arms that varied in affinity, and determined that the high-affinity CD3 arms were up to 100-fold more potent in vitro. However, in mouse models, the efficacy differences were less pronounced, probably because of prolonged exposure to TDB found with lower-affinity CD3 TDBs. In monkeys, assessment of safety and target cell depletion by the highand low-affinity TDBs revealed that only the low-affinity CD3/CLL1 TDB was well tolerated and able to deplete target cells. Our data suggest that an appropriately engineered CLL-1 TDB could be effective in the treatment of AML. (Blood. 2017;129(5):609-618)

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Section: Discussionmentioning

confidence: 99%

Section: /Cd38mentioning

confidence: 99%

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An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

Leong¹,

Sukumaran²,

Hristopoulos³

et al. 2017

Blood

137

128

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“…In accordance with the 2016 WHO criteria, ALL is classified in 13 categories based on the cellular immunophenotype and genomic abnormalities [2]. Prognostic factors have changed over time due to the generation of risk-adapted treatment regimens, including hematopoietic stem cell transplant (HSCT), as well as drugs such as rituximab, imatinib, and dasatinib directed against surface antigens and molecular targets, and more recently, blinatumomab and inotuzumab appear to be promising drugs in terms of patient survival [3][4][5][6][7]. In general, currently accepted high-risk factors are T-cell precursor leukemias, age, leukocytosis, and genetic factors [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Survival analysis of adult patients with ALL in Mexico City: first report from the Acute Leukemia Workgroup (ALWG) (GTLA)

et al. 2018

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Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the clonal expansion of hematopoietic lymphoid progenitors. With new target therapies, the survival of adults with ALL has improved in the past few decades. Unfortunately, there are no large ALL patient series in many Latin American countries. Data from the Acute Leukemia Workgroup that includes five Mexico City referral centers were used. Survival was estimated for adult patients with ALL during 2009–2015. In total, 559 adults with ALL were included. The median age was 28 years; 67% were classified into the adolescent and young adult group. Cytogenetic information was available in 54.5% of cases. Of the 305 analyzed cases, most had a normal caryotype (70.5%) and Philadelphia‐positive was present in 16.7%. The most commonly used treatment regimen was hyper‐CVAD. In approximately 20% of cases, there was considerable delay in the administration of chemotherapy. Primarily refractory cases accounted for 13.1% of patients. At the time of analysis, 26.7% of cases had survived. The 3‐year overall survival was 22.1%. The main cause of death was disease progression in 228 (55.6%). Clinical and public health strategies are needed to improve diagnosis, treatment and survivorship care for adult with ALL. This multicentric report represents the largest series in Mexico of adult ALL patients in which a survival analysis and risk identification were obtained.

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“…Additionally, if there is a slight immunophenotypic shift in the B-ALL surface antigen expression, an observation which is well-described in the relapse and post-treatment setting, diagnosis of MRD can be even more problematic (10). Further adding to the diagnostic complexity is the observation that B-ALL populations may lose their apparent surface CD19 expression after certain types of therapy (e.g., blinatumumab, CD19CAR T-cell therapy) (11,12). As CD19 is a backbone marker in most panels designed for detecting B-ALL, losing the ability to use this marker for MRD detection is critical.…”

mentioning

confidence: 99%

A bright and colorful future for DNA cell cycle analysis

Yuan¹

2016

Cytometry Pt A

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Blinatumomab for the treatment of acute lymphoblastic leukemia

Cited by 27 publications

References 49 publications

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

Survival analysis of adult patients with ALL in Mexico City: first report from the Acute Leukemia Workgroup (ALWG) (GTLA)

A bright and colorful future for DNA cell cycle analysis

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