Taking a “BiTE out of ALL”: blinatumomab approval for MRD-positive ALL

Curran, Emily; Stock, Wendy

doi:10.1182/blood-2018-12-852376

Cited by 43 publications

(42 citation statements)

References 40 publications

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“…Additionally, the 2 patients with morphological remission to whom Blinatumomab was administered for deepening MRD clearance, achieved MRD negativity after the 1 st cycle. It is evident that initial MRD response to Blinatumomab may serve as a strong surrogate marker in predicting survival [15]. Furthermore; our data strongly suggest that lower MRD levels prior to the first Blinatumomab administration are associated with superior response rates and outcome, as previously described [15].…”

Section: Discussionsupporting

confidence: 74%

“…Increased doses of 2 /day, have been evaluated in adult non-Hodgkin lymphomas [13,14], with heterogeneous initial results; in our patient, Blinatumomab resistance was doseindependent despite dose triplication. Mechanisms of Blinatumomab resistance have long been described [15,18,19], with CD19 target loss and lineage switch the most commonly reported [18,19]. In our study, 2/3 post-Blinatumomab relapses were CD19-negative and lineage switch (MPAL)…”

Section: Discussionsupporting

confidence: 53%

“…The optimal number of Blinatumomab cycles in the setting of relapsed/refractory ALL, remains an open issue [2,15]. According to our results, Blinatumomab responders are identified from day 29 of the 1 st cycle and therefore, no further treatment seems beneficial in case of day 29 disease refractoriness.…”

Section: Discussionmentioning

confidence: 66%

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Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients

Ampatzidou¹,

Kattamis²,

Baka³

et al. 2021

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Pediatric refractory or relapsed acute lymphoblastic leukemia (ALL) poses unique therapeutic challenges, with novel immunotherapy approaches offering potential cure opportunities. In this frame, the use of Blinatumomab may induce durable remissions, serving as a successful bridge to allergenic hematopoietic stem cell transplantation (allo-HSCT). Herein, we retrospectively summarize the Greek experience on pediatric relapsed/refractory B-cell precursor ALL patients that were treated with Blinatumomab in a compassionate, off-label setting as an effort to achieve disease clearance and proceed to allo-HSCT. In our cohort of 9 patients, 6/9 (66.7%) responded to Blinatumomab, achieving complete morphological remission (CR) after the 1st cycle, while minimal/measurable residual disease (MRD)-negativity (< 10-4) after the 1st cycle was achieved in 2/2 patients (100.0%) with prior CR. A successful bridge to HSCT was feasible in 5/9 patients (55.6%). Median relapse-free survival (RFS) was 3.0 months (range 0.5-21.4 months) and median overall survival (OS) was 8.7 months (range 1.4-47.1 months) for the whole pediatric cohort. There was a trend of prolonged survival among patients who achieved MRD response after the 1st Blinatumomab administration. MRD response (defined as the >=2-log reduction of MRD value before and after Blinatumomab administration), was associated with a median RFS/OS of 7.4/7.6 months, while lack of MRD response was associated with a median RFS/OS of 0.5/3.0 months, respectively. Novel therapeutic maneuvers, in order to overcome disease resistance, i.e. increased usage of Blinatumomab dose bination with donor lymphocyte infusions (DLIs), use of other immunotherapy salvage approaches (inotuzumabozogamicin), are herein discussed. Additionally, the optimal number of Blinatumomab cycles, the CD19-negative relapses and lineage switch, are also addressed. Our data although referred to a limited however refractory or relapsed and heavily pretreated number of patients, strongly suggest that Blinatumomab may well induce sustained remissions and serve as an effective bridge to HSCT. Whether immunotherapy combined with chemotherapy can outweigh the need for subsequent allo-HSCT, if incorporated into

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 53%

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Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients

Ampatzidou¹,

Kattamis²,

Baka³

et al. 2021

neo

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“…Currently, guidelines tried to recommend the regimens both by adult and pediatric settings as adult regimens were still widely used, especially in developing countries [13,14]. In addition, blinatumomab, which might further decrease CIR in MRD+ALL [15], was not available in the current study. Therefore, it remained to be addressed the role of haplo-SCT in the era of pediatric-inspired regimens and blinatumomab in the future.…”

Section: To the Editormentioning

confidence: 99%

Comparison of haplo-SCT and chemotherapy for young adults with standard-risk Ph-negative acute lymphoblastic leukemia in CR1

Jiang

Zhou

et al. 2020

J Hematol Oncol

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Human leukocyte antigen (HLA) haploidentical stem cell transplantation (haplo-SCT) as a postremission treatment for standard risk Philadelphia chromosome-negative acute lymphoblastic leukemia (SR Ph-ALL) in the first complete remission (CR1) has not been defined. In this multicenter, phase 3 study (NCT02042690), of the 131 consecutive Ph-ALL young adult patients (YA, aged 18-39 years) without high-risk features who achieved CR1, 114 patients without HLA-matched donors received consolidation with an adult chemotherapy regimen (n = 55) or haplo-SCT (n = 59). In the landmark analysis, haplo-SCT resulted in a lower 2-year cumulative incidence of relapse (CIR, 12.8% vs 46.7%, P = 0.0017) and superior 2-year leukemia-free survival (LFS, 80.9% vs 51.1%, P = 0.0116) and 2-year overall survival (OS, 91.2% vs 75.7 [64.8-93.2] %, P = 0.0408) than chemotherapy. In the time-dependent multivariate analysis with propensity score adjustment, postremission treatment (haplo-SCT vs chemotherapy) was an independent risk factor for the CIR (HR 0.195, 95% CI 0.076-0.499, P = 0.001), LFS (HR 0.297, 95% CI 0.131-0.675, P = 0.003), and OS (HR 0.346, 95% CI 0.140-0.853, P = 0.011). In all subgroups, CIR was lower in haplo-SCT. Myeloablative haplo-SCT with ATG+G-CSF might be one of the preferred therapies for YA patients with standard-risk Ph-ALL.

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“…CD33, CD123, and CD371 (CLL-1). [91][92][93][94][95][96][97][98][99][100][101] Currently, the efficacy of these agents is evaluated in clinical trials: CD33-directed bi-specific antibodies examined in the AML context, are, among others, the CD33/CD3 antibody constructs AMG330…”

Section: Targeting Of Aml Lsc By Applying Bi-or Tri-specific Antibomentioning

confidence: 99%

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

Valent

Bauer

Sadovnik

et al. 2020

Stem Cells Translational Medicine

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Despite new insights in molecular features of leukemic cells and the availability of novel treatment approaches and drugs, acute myeloid leukemia (AML) remains a major clinical challenge. In fact, many patients with AML relapse after standard therapy and eventually die from progressive disease. The basic concept of leukemic stem cells (LSC) has been coined with the goal to decipher clonal architectures in various leukemia-models and to develop curative drug therapies by eliminating LSC. Indeed, during the past few years, various immunotherapies have been tested in AML, and several of these therapies follow the strategy to eliminate relevant leukemic subclones by introducing LSC-targeting antibodies or LSC-targeting immune cells. These therapies include, among others, new generations of LSC-eliminating antibody-constructs, checkpoint-targeting antibodies, bi-specific antibodies, and CART or CAR-NK cell-based strategies. However, responses are often limited and/or transient which may be due to LSC resistance. Indeed, AML LSC exhibit multiple forms of resistance against various drugs and immunotherapies. An additional problems are treatment-induced myelotoxicity and other side effects. The current article provides a short overview of immunological targets expressed on LSC in AML. Moreover, cell-based therapies and immunotherapies tested in AML are discussed. Finally, the article provides an overview about LSC resistance and strategies to overcome resistance.

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Taking a “BiTE out of ALL”: blinatumomab approval for MRD-positive ALL

Cited by 43 publications

References 40 publications

Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients

Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients

Comparison of haplo-SCT and chemotherapy for young adults with standard-risk Ph-negative acute lymphoblastic leukemia in CR1

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

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