Bispecific T-cell Engager Antibody Construct Research Articles

SOHO State of the Art Updates and Next Questions | Optimal Timing of Blinatumomab for the Treatment of B-Acute Lymphoblastic Leukemia.

Blinatumomab is a CD19 targeting bi-specific T-cell engager antibody construct developed for the treatment of CD19 expressing B-cell malignancies. Numerous adult and pediatric B-ALL clinical trials have demonstrated blinatumomab's efficacy in the relapse setting as well as in patients with residual disease after upfront chemotherapy. The safety profile of blinatumomab is also favorable, making it a feasible option for most patients. Several key questions remain, including the role of blinatumomab as a replacement for toxic elements of standard chemotherapy regimens in the upfront setting, its role as a bridge to hematopoietic stem cell transplantation, or whether previous blinatumomab impacts the efficacy of subsequent CAR-T cell therapy.

Transcriptomic Features of Immune Exhaustion and Senescence Predict Outcomes and Define Checkpoint Blockade-Unresponsive Microenvironments in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Reinstating immunological control of AML is highly desirable to eradicate chemotherapy-resistant clones and provide long-term disease control. We recently identified bone marrow (BM) microenvironmental transcriptomic profiles that stratify patients with newly diagnosed AML into an immune-infiltrated and an immune-depleted subtype and that refine the accuracy of survival prediction beyond that afforded by current prognosticators (Vadakekolathu J et al., 2020). We have also shown that CD8 + T cells from patients with AML exhibit features of immune exhaustion and senescence (IES), including heightened expression of killer cell lectin-like receptor subfamily G member 1 (KLRG1) and B3GAT1 (encoding CD57) (Knaus H et al., 2018). Whether deranged T-cell functions affect the likelihood of responding to antitumor therapy, including immune checkpoint blockade (ICB), is an outstanding question in AML.In the current study, we analyzed 183 BM samples collected longitudinally at time of AML onset, response assessment and disease relapse from multiple cohorts of patients with AML treated with standard-of-care induction chemotherapy, and from 33 elderly AML patients with newly diagnosed or chemotherapy-refractory/relapsed AML treated with azacitidine, and the PD-1 checkpoint inhibitor pembrolizumab (NCT02845297). Primary patient specimens and associated clinical data were obtained via informed consent in accordance with the Declaration of Helsinki on research protocols approved by the Institutional Review Boards of the participating Institutions. RNA (150-200 ng) was extracted from BM aspirates and was processed on the nCounter FLEX analysis system (NanoString Technologies, Seattle, WA) using the PanCancer Immune profiling panel, as previously published (Vadakekolathu J et al., 2020). The correlation between transcriptomic features of IES, clinical characteristics, therapeutic response and patient outcome was validated using publicly available RNA-sequencing and NanoString data from 1,698 patients with AML, including samples from the TCGA-AML (n=147 cases), Beat-AML Master Trial (n=264 cases, of which 240 with survival data and 195 with chemotherapy response data) and Children's Oncology Group (COG)-TARGET AML series (n=145 cases).We initially showed that, compared with their non-senescent CD8 +CD57 -KLRG1 - counterpart, senescent CD8 +CD57 +KLRG1 + T cells are functionally impaired in terms of their ability to effect AML-blast killing mediated by an anti-CD33/CD3 bi-specific T-cell engager antibody construct (kindly provided by Amgen, USA; effector/target [E/T] ratio = 1:5). We then used gene set enrichment analysis (GSEA) to derive a transcriptomic signature of IES encompassing natural killer (NK)-cell and stem-like CD8 + T-cell markers, and showed that IES states correlate with lymphoid infiltration, adverse-risk molecular lesions (TP53 and RUNX1 mutations), experimental gene signatures of leukemia stemness (LSC17 score; Ng et al., 2016) and poor outcome in response to standard induction chemotherapy (Fig. 1A). In independent validation cohorts of children and adults with AML, the IES score was higher at baseline in patients with primary induction failure (following a standard 2 cycles of chemotherapy) compared with complete remission, increased in post-chemotherapy BM specimens, and predicted survival with greater accuracy than the ELN cytogenetic risk classifier (Fig. 1B). In the immunotherapy setting, high IES scores at baseline defined a checkpoint blockade-unresponsive AML tumor microenvironment and correlated with significantly shorter overall survival (9.1 versus 15.56 months in patients with high and low IES scores, respectively; HR = 3.32 (95% CI = 1.19-9.25); log-rank P = 0.021; Fig. 1C). Finally, the IES-related gene set also predicted for long-term outcomes and objective responses, based on RECIST criteria, to single-agent nivolumab or pembrolizumab, or combination anti-PD-1 + anti-CTLA-4, in 106 patients with melanoma (PRJEB23709 and GSE93157 series), a tumor type known to derive durable clinical benefit from ICB (Fig. 1D).Our findings encourage the pursuit of immune senescence reversal as a strategy to functionally reinvigorate T cells and could inform the delivery of ICB and other T cell-targeting immunotherapies to patients who are likely to benefit. [Display omitted] DisclosuresRadojcic: Syndax Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Allakos: Membership on an entity's Board of Directors or advisory committees. Minden: Astellas: Consultancy. Tasian: Aleta Biotherapeutics: Consultancy; Gilead Sciences: Research Funding; Kura Oncology: Consultancy; Incyte Corporation: Research Funding.

Blinatumomab for Patients with Richter's Syndrome: A Multicenter Phase 2 Trial from the Filo Group

BackgroundRichter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS patients is usually very poor with both low response rates to chemoimmunotherapy and short survival. While BCR and BCL2 inhibitors have transformed the management of CLL patients, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017).Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of patients with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. Recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in patients with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016).We hypothesized that blinatumomab would improve response in RS patients failing to achieve CR after initial debulking with R-CHOP.MethodsWe report here the first results of a phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for patients with untreated RS of DLBCL histology (NCT03931642). The patients with persisting (PR, SD) or progressive disease (PD) after 2 cycles of R-CHOP were eligible to receive an 8-week course of blinatumomab induction. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. An additional 4-week consolidation cycle was optional. Allo-HSCT was further allowed for eligible patients.ResultsA total of 34 patients out of 41 has already been enrolled in the trial to date. Median age was 66 years (range, 38-82) and sex ratio M/F was 23/12. CLL features at baseline were as follows: 57% had 17p deletion and 67% TP53 mutations. Sixty-five percent had complex karyotype and 79% unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-7): 19 (54%) patients previously received chemo-immunotherapy, 23 (66%) patients were exposed to ibrutinib and 11 (31%) to venetoclax.As of the data cut-off of June 1st, 2021, the blinatumomab induction course has been completed for 18 patients. Ten patients did not receive blinatumomab for the following reasons: 7 patients achieved CR after R-CHOP, 2 patients died because of febrile neutropenia after R-CHOP and 1 patient presented severe pneumonia after R-CHOP. Three patients are still on R-CHOP and 3 others on blinatumomab to date.Regarding toxicity during blinatumomab, data are available for the 18 patients having completed the blinatumomab induction to date. All patients had at least one grade 1 adverse event (AE), 10 had grade ≥3 AE. The most common AE (> 1 case), regardless of relationship to blinatumomab, were fever (4 patients), CRS (2 patients), sepsis (2 patients), vein thrombosis (2 patients), anemia (4 patients), neutropenia (3 patients), lymphopenia (5 patients), thrombocytopenia (3 patients) and hyperglycemia (5 patients). In terms of neurologic events, 5 (28%) experienced neurotoxicity (all recovered) including grade 3 encephalopathy, grade 4 confusion, grade 3 anxiety, grade 1 myoclonus, grade 2 ataxia, grade 1 sleep disorder and grade 1 ICANS (each in 1 pt). Blinatumomab was temporarly stopped in 3 patients and permanently in 2.In terms of efficacy, after R-CHOP debulking therapy (n=31 evaluable patients), 7 patients achieved CR, 6 patients were in PR, 7 patients were stable and 11 patients were progressive. At evaluation after the blinatumomab induction (n=18 evaluable patients), 4 (22.2%) patients achieved CR, 4 (22.2%) patients PR, 2 (11.1%) patients were stable and the remaining 8 (44.5%) were progressive. Considering the whole strategy (including R-CHOP debulking) (n=28), 15 (54%) patients achieved overall response including 11 (39%) CR.ConclusionsOur preliminary data suggest that blinatumomab suggests encouraging anti-tumor activity and acceptable toxicity in patients with RS. DisclosuresYsebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Ferrant: AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Laribi: Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; Jansen: Research Funding; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding. Feugier: Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. OffLabel Disclosure:blinatumomab is approved for acute lymphoblastic leukemia. The aim of this phase 2 study is to evaluated it in patients with Richter's syndrome.

Optimal Timing of Blinatumomab for the Treatment of B-Lymphoblastic Leukemia

Introduction Blinatumomab is a CD19-targeting bi-specific T-cell engager antibody construct developed for the treatment of CD19-expressing B-cell malignancies. After early impressive in vitro and in vivo pre-clinical results,1–3 blinatumomab was quickly incorporated into clinical investigations. After a phase I non-Hodgkin lymphoma (NHL) trial established a safe and effective dose, delivered via continuous intravenous (IV) infusion,4 trials exploring its use in B-lymphoblastic leukemia (B-ALL) soon followed. The results of these trials have been largely positive, though the extent of response and benefit appears to vary based on disease status and burden at the time of treatment. Thus, the optimal incorporation of blinatumomab into B-ALL therapy is still being refined.

Baseline Biomarkers Influencing Clinical Outcomes in Adults with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL) Treated with Blinatumomab Versus Standard-of-Care Chemotherapy (SOC) from a Randomized Phase 3 Study

Introduction: Blinatumomab, an anti-CD3/CD19 bispecific T-cell engager antibody construct, showed antileukemic activity and significantly longer overall survival (OS) vs SOC in adults with advanced Philadelphia chromosome-negative R/R ALL (median OS 7.7 vs 4.0 months; P=0.01) (N Engl J Med 2017;376:836−847). Here we aimed to identify baseline biomarkers that were prognostic (disease-related) or predictive (treatment-related) of clinical outcomes.Methods: Adults with R/R ALL (refractory to primary induction therapy or salvage therapy, first relapse <1 year, second or later relapse, or relapse after allogeneic hematopoietic cell transplantation [alloHCT]) were randomized to receive either blinatumomab or SOC. Blinatumomab was given by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 μg/d on d1‒7 of cycle 1 and 28 μg/d thereafter). Up to 4 additional maintenance cycles (4 wks on/8 wks off) were allowed for up to 1 year. Evaluated biomarkers included leukocytes, monocytes, lymphocytes, granulocytes, platelets, neutrophils, CD45+ CD3+ CD4+ T cells, CD45+ CD3+ CD8+ T cells, CD45+ CD3- CD19+ B cells, CD3- CD16+ CD56+ cells, bone marrow (BM) blasts, CD3+ T cells, CD19+ cells, and ratios of CD3+/CD19+ and CD3+%/BM blast%. A multivariate model was used to select potential biomarkers associated with treatment outcomes. Effect on outcome was determined if either the main effect or interaction term between the biomarker and treatment had a P value ≤0.3. Prognostic and predictive associations of baseline biomarkers with OS, hematologic response (complete remission [CR] or CR with full, partial, or incomplete hematologic recovery [CR/CRh/CRi]) within the first 12 wks, and minimal residual disease (MRD) response were assessed by Cox regression for OS and multivariate logistic regression for hematologic response and MRD response. Predictive biomarkers were identified using interaction tests with treatment group.Results: A total of 405 patients received blinatumomab (n=271) or SOC (n=134). Baseline characteristics including age, prior alloHCT, salvage status, granulocytes, platelets, and lymphocyte subpopulations (CD45+ CD3+ CD8+, CD45+ CD3- CD19+, and CD3+) were generally balanced between treatment arms. Associations of baseline biomarkers with clinical outcomes are presented in the table. Higher platelet counts were associated with decreased risk of death (HR 0.43; 95% CI 0.29-0.65) and increased CR (odds ratio [OR] 4.12; 95% CI 2.04-8.33) and CR/CRh/CRi (HR 1.64; 95% CI 0.90-2.99). Higher granulocyte counts were associated with decreased risk of death (HR 0.75; 95% CI 0.57-0.99), whereas total leukocyte counts were not (HR 1.04; 95% CI 0.70-1.54). Lower BM blast percentage was associated with increased CR (OR 0.90; 95% CI 0.82-0.97) and CR/CRh/CRi (OR 0.87; 95% CI 0.80-0.95) but not OS (HR 1.04; 95% CI 0.98-1.09). Higher CD3+ T cells were associated with increased MRD response (OR 1.75; 95% CI 0.99-3.08). Higher counts of CD45+ CD3- CD19+ cells increased the risk of death for blinatumomab patients (HR 1.19; 95% CI 1.09-1.29) but also was not associated with a survival advantage for SOC patients (HR 1.03; 95% CI 0.93-1.15). Higher CD45+ CD3+ CD8+ T cells were associated with increased CR (OR 1.39; 95% CI 1.18-1.65) and CR/CRh/CRi (OR 1.44; 95% CI 1.22-1.70) in patients treated with blinatumomab but did not correlate with increased hematologic response in SOC patients. Multiple logistic regression modeling for adverse events (AEs) of interest showed that BM blasts and lymphocyte markers (CD3+ and CD45+ CD3+ CD8+) were not associated with grade ≥3 neurologic events, infections, or cytokine release syndrome.Conclusions: Higher platelet and granulocyte counts, lower BM blasts, and higher numbers of CD3+ T cells were prognostic for improved OS, hematologic response, and MRD response, respectively, in patients with R/R ALL who received blinatumomab vs SOC. A higher frequency of CD45+ CD3+ CD8+ cells was predictive of increased hematologic response to blinatumomab, whereas a higher frequency of CD45+ CD3- CD19+ cells was predictive of decreased OS. BM blast percentage and lymphocyte markers were not associated with AEs of interest. Overall, these data demonstrate that responses to blinatumomab can be seen across a variety of subgroups, including those expressing specific baseline biomarkers. Further study is needed to identify subgroups most likely to benefit from blinatumomab. [Display omitted] DisclosuresWei:AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria. Ribera:Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria. Larson:Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Research Funding. Ritchie:Amgen Inc.: Honoraria. Chen:Amgen Inc.: Employment, Other: Stock holder. Dos Santos:Amgen Inc.: Employment. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Kantarjian:Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding.

Blinatumomab in B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease: Initial Results of a Phase II Trial

Blinatumomab in B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease: Initial Results of a Phase II Trial

Maintenance Therapy with Blinatumomab in Adults with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL): Overall Survival in Adults Enrolled in a Phase 3 Open-Label Trial

IntroductionHematopoietic stem cell transplant (HSCT) after induction/consolidation therapy with standard chemotherapy or targeted therapies, such as blinatumomab or inotuzumab (Kantarjian H, et al. N Engl J Med . 2016;375:740-53), is considered the only treatment option with curative intent for patients with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (r/r Ph- B-precursor ALL). A recent randomized phase 3 study of blinatumomab, a bispecific T-cell engager antibody construct, in patients with r/r Ph- B-precursor ALL, included a maintenance treatment phase to allow patients in hematologic remission to continue blinatumomab (Kantarjian H, et al. N Engl J Med . 2017;376:836-847). In this exploratory analysis, we examined overall survival (OS) for patients who received blinatumomab maintenance therapy and compared outcomes with data pooled from patients who did not receive maintenance therapy in the phase 3 and phase 2 (Topp MS, et al. Lancet Oncol . 2015;16:57-66) blinatumomab trials.MethodsAdult patients (≥18 years) in this phase 3 trial were randomized to either blinatumomab or standard of care (SOC) chemotherapy. Patients randomized to blinatumomab received this treatment by continuous intravenous infusion (4 weeks on, 2 weeks off; 9 μg/day on days 1-7 of Cycle 1 and 28 μg/day thereafter) during induction and consolidation cycles. Patients could receive HSCT at any time after cycle 1. Patients who received blinatumomab, and had bone marrow blasts <5% after two induction and three consolidation cycles of blinatumomab, were eligible for blinatumomab maintenance, administered for up to an additional 12 months (4 weeks on therapy, 8 weeks off). Maintenance therapy was discontinued in case of transition to HSCT, investigator discretion, toxicity, relapse, or use of protocol-excluded medications. The cumulative probability of OS over time was estimated using the Simon-Makuch method and the effect of maintenance was analyzed using the Mantel-Byar method. OS was measured from the start of maintenance therapy for patients who were in remission until the start of Cycle 6 (for those who received maintenance) or at Day 211 (landmark date for those who did not receive maintenance). Data from the phase 3 study and an earlier phase 2 study in which maintenance was not offered were pooled to increase the sample size for this OS analysis.ResultsAs of the primary analysis cutoff, 119 of 271 (43.9%) patients receiving blinatumomab achieved a best response of CR/CRh/CRi within two treatment cycles, and 27 patients continued to the blinatumomab maintenance phase. Three patients completed the maintenance phase, 4 transitioned to HSCT, and one discontinued due to adverse events (AE). Twenty-one (77.8%) patients had a best response of CR during maintenance, 1 (3.7%) patient each had CRh or blast free hypoplastic or aplastic bone marrow, and 2 (7.4%) patients each had hematologic relapse or were not evaluable. The Mantel-Byar analysis demonstrated a relative OR for OS of 0.59 (95% CI, 0.20 - 1.73) P = 0.33 comparing maintenance vs. no maintenance (Figure), representing a 41% reduction in the risk of death associated with maintenance therapy, though not statistically significant. Among patients receiving blinatumomab who entered the maintenance phase, the incidence of adverse events of interest generally was less compared with the incidence during the induction or consolidation phases (Table).ConclusionsIn r/r ALL patients who achieved a hematologic response following blinatumomab induction/consolidation, high response rates with blinatumomab maintenance therapy (beyond cycle 5) were observed, with longer OS compared with patients receiving no maintenance. During maintenance with blinatumomab, no new safety concerns were identified. A lower incidence of adverse events of interest was seen during the maintenance phase, compared with events recorded during the induction/consolidation phases of this, and prior blinatumomab studies.Research supported by Amgen Inc. [Display omitted] DisclosuresRambaldi:Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy; Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses. Rigal-Huguet:Bristol Myers-Squibb, Novartis, Pfizer, Amgen, Incyte, Jazz Pharma: Consultancy; Bristol Myers-Squibb, Novartis, Pfizer, Amgen, Incyte, Jazz Pharma: Honoraria. Nie:Amgen: Employment, Equity Ownership. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Topp:Amgen: Consultancy, Honoraria, Other: Travel, Research Funding; Regeneron: Consultancy, Honoraria, Research Funding; Celgene: Other: Travel; Roche: Consultancy, Research Funding; Macrogenics: Consultancy, Research Funding.

Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports

BackgroundThe outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response.Case presentationPatient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR.ConclusionIn our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

Blinatumomab after R-CHOP Debulking Therapy for Patients with Richter Transformation: Preliminary Results of the Multicenter Phase 2 Blinart Trial from the Filo Group

Background Richter syndrome (RS) refers as to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients (pts) with chronic lymphocytic leukemia (CLL). The outcome of RS pts is usually very poor with both low response rates to chemoimmunotherapy and short survival, except for the minority of them whose tumor cells are clonally unrelated to the underlying CLL. While BCR and BCL2 inhibitors have transformed the management of CLL pts, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of pts with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. More recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in pts with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS pts failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a currently ongoing phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for pts with untreated RS of DLBCL histology (NCT03931642). The pts achieving complete remission (CR) after 2 cycles of R-CHOP21 discontinued study while those with persisting (PR, SD) or progressive disease (PD) were eligible to receive an 8-week course of blinatumomab induction. An additional 4-week consolidation cycle was optional and might be proposed according to the treating-physician decision, especially in pts who were ineligible for stem-cell transplantation. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. Interim analysis (Simon two-stage design) was planned after completion of blinatumomab induction in 10 pts. Results A total of 15 pts out of 35 has already been enrolled in the trial to date. Median age was 67 years (range, 38-80) andsex ratioM/F was 12/3. CLL features at baseline were as follows: 9/15 (60%) pts hadTP53alterations and 10/13 (77%) unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-4): 10 (67%) pts previously received chemo-immunotherapy, 10 (67%) pts were exposed to BCR inhibitors and 3 (20%) to venetoclax. As of the data cut-off of July 1st, 2020, the blinatumomab induction course has been completed for 5 pts while it is still on-going in 3 others. Three pts are still on R-CHOP debulking. Four pts discontinued study before receiving blinatumomab for the following reasons: 2 pts achieved CR after R-CHOP, 1 patient died because of febrile neutropenia after R-CHOP and 1 patient discontinued study before starting R-CHOP (no RS criteria after pathology review). Regarding toxicity during blinatumomab, data are available for the 5 pts having completed the blinatumomab induction to date. Four pts had at least one grade 1 adverse event (AE), 2 had grade ≥3 AE. The most common AE, regardless of relationship to blinatumomab, were grade 1 fever (2 pts) and grade 2 leukopenia (2 pts). Other grade &amp;gt;1 AE were observed in 1 pt only (grade 3 anxiety, grade 2 anemia, grade 2 neutropenia, grade 3 lymphopenia). In terms of neurologic event, 1 pt had grade 1 AE (paresthesia, myoclonus and muscle contraction) and another one presented grade 4 confusion while on first 9 μg/d dose leading to permanent discontinuation of blinatumomab. In terms of efficacy, after R-CHOP debulking therapy (n=10 evaluable pts), 2 pts achieved CR (and did not pursuit on study), 5 pts were in PR and 3 pts were progressive. At evaluation after the blinatumomab induction (n=5 evaluable pts), 2 pts achieved CR, 1 patient PR and 2 pts were progressive. Conclusions Our preliminary data suggest that blinatumomab shows encouraging anti-tumor activity and acceptable toxicity in pts with RS. Further analyses are warranted to validate these conclusions. Updated efficacy/safety in the remaining pts enrolled in the trial will be presented at the meeting. Disclosures Guieze: astrazanecka:Honoraria, Other: advisory board;gilead:Honoraria, Other: travel funds;janssen cilag:Honoraria, Other: advisory board, travel funds;roche:Other: travle funds;abbvie:Honoraria, Other: advisory board, travel funds.Ysebaert:AbbVie:Consultancy;Janssen:Consultancy;Roche:Consultancy.Fornecker:Roche:Consultancy;Takeda:Consultancy.Broséus:Gilead:Honoraria;AstraZeneca:Consultancy, Honoraria;Janssen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Feugier:astrazeneca:Consultancy, Honoraria, Research Funding;abbvie:Consultancy, Honoraria, Research Funding;roche:Consultancy, Honoraria, Research Funding;gilead:Consultancy, Honoraria, Research Funding;janssen:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells. It has been approved as a second line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.

Long-term outcome of patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with blinatumomab.

Blinatumomab, the first-in-class CD3/CD19 bispecific T-cell engager antibody construct, has recently been approved for treating patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia. However, the clinical proof of concept of blinatumomab efficacy was initially demonstrated in patients with R/R B-cell non-Hodgkin lymphoma (B-NHL) in the MT103-104 phase 1 dose-escalation and expansion trial (NCT00274742), which defined 60 µg/m2 per day as the maximum tolerated dose (MTD). The clinically most relevant adverse effects were neurologic symptoms and cytokine release syndrome. Currently, there are no data on long-term outcomes and toxicity for B-NHL patients receiving blinatumomab treatment, so we performed a single-center, long-term follow-up analysis of 38 patients who participated in the MT103-104 phase 1 trial. We found no evidence for long-term toxicities, especially no blinatumomab-induced neurocognitive impairments. For the entire study population, the median overall survival (OS) was 4.6 years. Remarkably, patients who had received ≥60 µg/m2 per day and responded to blinatumomab achieved a median OS of 7.7 years. Of note, 6 of the surviving patients treated at the MTD have been treatment-free for more than 7 years. In contrast, patients who were treated at dose levels below the MTD had a median OS of only 1.1 years. These results indicate that 60 µg/m2 per day seems to represent the targeted dose level of blinatumomab required for durable remission in R/R B-NHL. Here, we provide the first clinical evidence that blinatumomab lacks long-term toxicity and has the potential to induce sustained remissions in patients with R/R B-NHL.

Phase 1 study of AMG 757, a half-life extended bispecific T cell engager (BiTE) antibody construct targeting DLL3, in patients with small cell lung cancer (SCLC).

TPS8577 Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.

Phase 2 Study of Blinatumomab in Japanese Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)

Phase 2 Study of Blinatumomab in Japanese Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)

Phase II Study of Blinatumomab in Patients with B-Cell Lineage Acute Lymphocytic Leukemia with Positive Minimal/Measurable Residual Disease

Phase II Study of Blinatumomab in Patients with B-Cell Lineage Acute Lymphocytic Leukemia with Positive Minimal/Measurable Residual Disease

A gB/CD3 bispecific BiTE antibody construct for targeting Human Cytomegalovirus-infected cells

Bispecific T cell engager (BiTE) antibody constructs are successfully used as cancer therapeutics. We hypothesized that this treatment strategy could also be applicable for therapy of human cytomegalovirus (HCMV) infection, since HCMV-encoded proteins are abundantly expressed on the surface of infected cells. Here we show that a BiTE antibody construct directed against HCMV glycoprotein B (gB) and CD3 efficiently triggers T cells to secrete IFN-γ and TNF upon co-culture with fibroblasts infected with HCMV strain AD169, Towne or Toledo. Titration of gB expression levels in non-infected cells confirmed that already low levels of gB are sufficient for efficient triggering of T cells in presence of the BiTE antibody construct. Comparison of redirecting T cells with the bispecific antibody versus a chimeric antigen receptor (CAR) based on the same scFv showed a similar sensitivity for gB expression. Although lysis of infected target cells was absent, the BiTE antibody construct inhibited HCMV replication by triggering cytokine production. Notably, even strongly diluted supernatants of the activated T cells efficiently blocked the replication of HCMV in infected primary fibroblasts. In summary, our data prove the functionality of the first BiTE antibody construct targeting an HCMV-encoded glycoprotein for inhibiting HCMV replication in infected cells.

Antiviral Activity of HIV gp120-Targeting Bispecific T Cell Engager Antibody Constructs

Today's gold standard in HIV therapy is combined antiretroviral therapy (cART). It requires strict adherence by patients and lifelong medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency but cannot cure patients. The bispecific T cell-engaging (BiTE) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. Here, we generated BiTE antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1 + 2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3ε scFv. These engineered human BiTE antibody constructs showed engagement of T cells for redirected lysis of HIV gp120-transfected CHO cells. Furthermore, they substantially inhibited HIV-1 replication in peripheral blood mononuclear cells (PBMCs) as well as in macrophages cocultured with autologous CD8+ T cells, the most potent being the human CD4(1 + 2) BiTE [termed CD(1 + 2) h BiTE] antibody construct and the CD4(1 + 2)L17b BiTE antibody construct. The CD4(1 + 2) h BiTE antibody construct promoted HIV infection of human CD4-/CD8+ T cells. In contrast, the neutralizing B12 and the VRC01 BiTE antibody constructs, as well as the CD4(1 + 2)L17b BiTE antibody construct, did not. Thus, BiTE antibody constructs targeting HIV gp120 are very promising for constraining HIV and warrant further development as novel antiviral therapy with curative potential.IMPORTANCE HIV is a chronic infection well controlled with the current cART. However, we lack a cure for HIV, and the HIV pandemic goes on. Here, we showed in vitro and ex vivo that a BiTE antibody construct targeting HIV gp120 resulted in substantially reduced HIV replication. In addition, these BiTE antibody constructs display efficient killing of gp120-expressing cells and inhibited replication in ex vivo HIV-infected PBMCs or macrophages. We believe that BiTE antibody constructs recognizing HIV gp120 could be a very valuable strategy for a cure of HIV in combination with cART and compounds which reverse latency.

Exposure-adjusted adverse events (AEs) comparing blinatumomab to standard of care (SOC) chemotherapy in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from a randomized phase III study.

7032 Background: Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown improved overall survival vs SOC in pts with r/r ALL in a randomized phase 3 study ( Haematologica 2016;101:S129). To better evaluate safety, we compared AEs of blin vs SOC after adjusting for varying treatment exposure times. Methods: Adults ≥ 18 yrs with r/r ALL (refractory, 1st relapse &lt; 1 yr, ≥ 2 relapses or relapse after transplant) were randomized to receive blin or SOC (1 of 4 predefined regimens). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 µg/d on d1−7 in cycle 1, then 28 µg/d); up to 4 maintenance cycles (4 wks on/8 wks off) were allowed for ≤ 12 mo. Exposure-adjusted (exp-adj) event rates were calculated as no. of events*100/total exposure time (Table). Results: Median (range) no. of cycles were 1 (1−4) for SOC and 2 (1−9) for blin. The highest exp-adj rates (per 100 pt-yrs) were for pyrexia (507 SOC vs 376 blin), anemia (987 vs 229), thrombocytopenia (750 vs 126) and neutropenia (351 vs 121), all lower in blin. Febrile neutropenia (365 vs 93) and infections (1216 vs 436) were also both lower in blin (p &lt; 0.0001). Exp-adj rates for neurologic events were 743 SOC vs 472 blin, with median time (range) to onset of 7 (1−43) d and 7 (1−190) d, respectively, and gr ≥ 3 cytokine release syndrome (CRS) rates were 0 SOC vs 10 blin. The most frequent AEs in both cycles 1 and 2 were pyrexia, nausea and anemia in both arms; CRS events decreased in the blin arm between cycles 1 and 2 (14% vs 2%). Most fatal AEs were related to infection in both arms. Conclusions: Here blin showed an AE profile consistent with that previously reported for r/r ALL, including similar rates of manageable CRS and neurologic events. Exp-adj AE rates were generally higher in SOC vs blin, including for cytopenias and infections. Clinical trial information: NCT02013167. [Table: see text]

Blinatumomab use in pediatric patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from an open-label, multicenter, expanded access study.

10530 Background:Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown antileukemia activity and tolerability in pts with r/r ALL. We further evaluated safety and efficacy of blin in the first 40 pediatric pts with r/r ALL enrolled in an expanded access study (NCT02187354). Methods: Eligible pts (28 d to &lt; 18 yrs) had ≥ 5% blasts and r/r ALL (refractory, ≥ 2 relapses or relapse after transplant [HCT]). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (≥ 5 to &lt; 25% blasts: 15 µg/m2/d; ≥ 25% blasts: 5 µg/m2/d on d1−7 in cycle 1, then 15 µg/m2/d). The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs); key efficacy endpoints were complete response (CR) and minimal residual disease (MRD, by PCR or flow cytometry) in the first 2 cycles, relapse-free survival, overall survival and HCT rate. Results: Of the first40 treated pts (median age, 9 [range, 1−17] yrs), 24 (60%) had ≥ 2 relapses, 20 (50%) relapsed after HCT and 5 (13%) were primary refractory; 18 (45%) had ≥ 50% blasts and 21 (53%) had prior HCT. Safety and key efficacy outcomes are shown in the table, including 63% CR in the first 2 cycles. There were 8 relapses and 20 deaths after treatment. Regardless of causality, the most frequent TEAEs were pyrexia (78%), cytokine release syndrome (CRS; 23%) vomiting (23%) and anemia (20%); all 9 CRS events were grade (gr) 1 or 2 and 1 tumor lysis syndrome was gr 3. 10 (25%) pts interrupted treatment and 2 (5%) discontinued due to TRAEs; 13 (33%) pts had gr ≥ 3 TRAEs, including 2 of 3 neurologic events (depressed level of consciousness and headache; both gr 3); 2 fatal AEs were considered unrelated to blin. Conclusions:Here single-agent blin showed antileukemia activity in pediatric pts with high-risk r/r ALL including t(17;19) and AEs consistent with those previously reported for r/r ALL. Clinical trial information: NCT02187354. [Table: see text]

Health-Related Quality of Life (HRQoL) of Blinatumomab Versus Standard of Care (SOC) Chemotherapy in Patients with Relaspsed or Refractory Philadelphia Negative B-Cell Precursor Acute Lymphoblastic Leukemia in a Randomized, Open-Label Phase 3 Study (TOWER)

▪IntroductionBlinatumomab, a bispecific T-cell engager antibody construct, binds specifically to CD19 (B cells) and CD3 (T cells) to facilitate lysis of CD19-positive target B-lineage cells. Based on a single-arm phase 2 study, blinatumomab received approvals in the US (accelerated) and EU (conditional) for the treatment of Philadelphia chromosome-negative (Ph-) relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the phase 3, randomized, open-label TOWER study, blinatumomab immunotherapy significantly improved overall survival (OS) as compared to SOC chemotherapy in adult patients with Ph- r/r BCP-ALL. This abstract reports the impact of blinatumomab compared with SOC on HRQoL using data from TOWER.MethodsPatients (n=405) with r/r BCP-ALL were randomized 2:1 to receive either blinatumomab (n=271) or SOC chemotherapy (n=134). Patients in remission after 2 induction cycles were eligible to continue therapy. A 12-month maintenance phase was allowed for patients who received up to 3 consolidation cycles and continued with a bone marrow response. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) on day 1 (baseline), day 8, day 15, day 29 in each cycle of investigational therapy and safety follow up. The HRQoL analyses included subjects with baseline and ≥1 post-baseline result of any EORTC QLQ-C30 multi-item scale or single-item measure. The change from baseline was summarized by visit and by treatment arm. Time-to-deterioration (TTD) analyses were conducted to determine the treatment effect based on timing from the initiation of treatment to a 10-point deterioration from baseline in HRQoL using EORTC QLQ-C30 or time to an event free survival (EFS) event. EFS was defined as day 1 for subjects who never reached hematologic response, and as time to relapse following response or death for those who reached hematologic response.ResultsOf the 376 patients who received at least 1 dose of study drug, 342 patients had baseline and ≥1 post-baseline HRQoL results. Mean pre-treatment baseline scores were balanced between the blinatumomab (n=247) and SOC (n=95) groups. In general, patients receiving blinatumomab had better post-treatment HRQoL versus SOC across all multi-item scales or single-item measures based on visual inspection (Table1). As early as day 8 of cycle 1 in the SOC arm, mean changes from baseline suggested worsening in HRQoL in almost all subscales/single items, whereas in blinatumomab arm, mean changes from baseline suggested improvement in HRQoL in almost all subscales (Table 1). The hazard ratios (HRs) from the TTD analyses ranged from 0.588 to 0.798 in favor of blinatumomab, with the upper bounds to the 95% CI <1.0 across all subscales and single items except insomnia (Table 2).ConclusionsBlinatumomab delayed the time to clinically meaningful deterioration in HRQoL or EFS event versus SOC across almost all functional domains and symptoms relevant to oncology patients. Moreover, HRQoL benefits with blinatumomab relative to SOC could be observed as early as 8 days after treatment initiation. The benefits in HRQoL, in addition to the significant improvement in efficacy, including OS, and acceptable safety profile of blinatumomab versus SOC, support a favorable benefit-risk profile of blinatumomab in patients with Ph- r/r BCP-ALL. Limitations of the analysis include potential bias due to different cycle lengths between blinatumomab and SOC regimens (6-week cycle for blinatumomab vs variable cycle lengths for SOC) and missing data. [Display omitted] [Display omitted] DisclosuresTopp:Jazz: Consultancy; Roche: Honoraria, Other: travel; Pfizer: Consultancy, Other: Travel; Boehringer: Consultancy, Other: Travel, Research Funding; Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Dombret:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Maertens:Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy. Schuh:Amgen: Membership on an entity’s Board of Directors or advisory committees. Franklin:Amgen: Employment, Other: Stocks. Nie:Amgen: Employment. Cong:Amgen: Employment.

Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma

AbstractFew patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19-positive B cells. This phase 2 study evaluated stepwise (9-28-112 μg/d with weekly dose increases; n = 23) or flat (112 μg/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Among 21 evaluable patients, the overall response rate after 1 blinatumomab cycle was 43%, including complete responses (CRs) in 19%. Three patients had late CR in follow-up without other treatment. The most common adverse events with stepwise dosing were tremor (48%), pyrexia (44%), fatigue (26%), and edema (26%). Grade 3 neurologic events with stepwise dosing were encephalopathy and aphasia (each 9%) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4%). Of 5 (22%) patients who discontinued stepwise dosing because of adverse events, 4 (17%) had neurologic events. Most neurologic events resolved. The flat-dose cohort was stopped because of grade 3 neurologic events in both patients. Blinatumomab monotherapy appears effective in patients with relapsed/refractory DLBCL, a heavily pretreated patient population with a high unmet medical need. Further studies need to define the optimal approach to achieve the target dose without early dropout. The study was registered at www.clinicaltrials.gov as #NCT01741792.

Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment

AbstractThis long-term follow-up analysis evaluated overall survival (OS) and relapse-free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (<10−4 blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS ≥30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ∼18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS <30 months.