
==== Front
Mediterr J Hematol Infect Dis
Mediterr J Hematol Infect Dis
Mediterranean Journal of Hematology and Infectious Diseases
Mediterranean Journal of Hematology and Infectious Diseases
2035-3006
Università Cattolica del Sacro Cuore

10.4084/MJHID.2024.070
mjhid-16-1-e2024070
Review Article
Blinatumomab in the Therapy of Acute B-Lymphoid Leukemia
Testa Ugo 1
Pelosi Elvira 1
Castelli Germana 1
Chiusolo Patrizia 23
1 Istituto Superiore Sanità, Roma, Italy
2 Department of Radiological and Hematological Sciences, Catholic University, Rome, Italy
3 Department of Laboratory and Hematological Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Correspondence to: Ugo Testa. E-mail: ugo.testa@iss.it
2024
01 9 2024
16 1 e202407007 8 2024
12 8 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Blinatumomab, a CD19-CD3 bispecific T cell engager (BiTE), has two recombinant single-chain variable fragments that temporarily link CD3+ T cells and CD19+ B cells, leading to the T cell-mediated lysis of neoplastic B cells. Improved minimal residual disease (MRD)-negative response rates and long-term overall survival have been observed in B-ALL patients who received this drug. These therapeutic successes have led to FDA approval for refractory/relapsed and MRD-positive B-ALL patients. Furthermore, recent studies in newly diagnosed B-ALL patients have led in Philadelphia chromosome-positive patients to the development of chemotherapy-free regimens based on tyrosine kinase inhibitors plus Blinatumomab and in Philadelphia chromosome-negative patients to improvement in outcomes using chemotherapy regimens that have incorporated Blinatumomab in the consolidation phase of treatment.

Blinatumomab
ALL
Immunotherapy
Bispecific antibody
==== Body
pmcIntroduction

The development of bispecific antibodies (bsAbs) has represented an area of considerable interest in the past decade, related to their unique properties compared to traditional monospecific monoclonal antibodies.1–2 Thus, a consistent number of bsAbs has been approved for cancer therapy, thus showing the rapid evolution of these antibodies as a novel category of therapeutic agents.1–2

T cell engagers (TCEs) are bsAbs that specifically bind to a tumor cell surface antigen and to the CD3 chain of the TCR and have the property of specifically activating an immune response T-cell mediated at the level of sites of tumor development..1,2 Blinatumomab, an example of next-generation TCE, requires simultaneous spatial binding of the targets: CD19 on the surface of leukemic cells and CD3 on the surface of T cells.1,2

It is designed to lack an Fc portion, composed of the tandem scFv-based CD19xCD3 antibody, which was first approved in 2014 for the treatment of relapsed/refractory B-ALL and which is giving growing contributions to the treatment of these leukemic patients in various clinical settings.3

Blinatumomab in Relapsed/Refractory B-ALL

Blinatumomab was approved for use in patients with relapsed/refractory B-ALL based on single-group trials showing enhanced efficacy and acceptable safety profile. A large phase III trial explored a consistent group of 376 adult Ph− R/R B-ALL patients randomly assigned to treatment with Blinatumomab or chemotherapy. Blinatumomab significantly improved OS with respect to chemotherapy (7.7 months vs 4.0 months, respectively) and event-free survival, as well as median duration of remission (Table 1).4

The analysis of long-term survival of a large group of R/R, Philadelphia-negative, B-ALL patients enrolled in two phase II studies involving the treatment with Blinatumomab showed a mOS of 7.5 months; importantly, both OS and RFS plateaued with 3-year.5 For patients who achieved a CR with Blinatumomab, followed by allogeneic HSCT while in remission, the mOS was 18.1 months.5 About 17% of R/R B-ALL patients treated with Blinatumomab survived >36 months, including 55% of patients who underwent aHSCT and 45% without transplantation. The retrospective analysis of 532 R/R B-ALL patients treated with Blinatumomab who received this drug as first salvage had a longer mOS and RFS and higher rates of remission, MRD response, and aHSCT in continuous remission compared to those who received Blinatumomab as second or later salvage.6

The retrospective observational study (NEUF) explored the safety and efficacy of Blinatumomab in R/R patients evaluated in the context of real-world use of this drug in current clinical practice; 140 R/R B-ALL patients were evaluated (106 Ph− and 34 Ph+).6 This real-world data set of adult R/R B-ALL patients treated with Blinatumomab confirms the efficacy outcomes observed in randomized clinical trials.7

A phase I clinical study evaluated the safety and efficacy of Blinatumomab in combination with PD1 and CTLA4 inhibitors in R/R B-ALL patients.8 Among 22 evaluable patients, the CR was 68%, and all achieved MRD negativity: at 1 year, the RFS was 27%, and the OS was 63%.8 These observations showed that combination therapy with Blinatumomab and immune checkpoint inhibitors (ICIs) in R/R B-ALL patients was safe and was associated with a high rate of MRD-negative responses. However, these results are only preliminary and required to be confirmed.

An open-label, single-arm, phase II, multicentre ALCANTARA study explored the response of 45 B-ALL Ph+ patients who had relapsed or were refractory to at least one TKI to Blinatumomab.9 16/45 patients achieved a CR within the first two cycles of Blinatumomab therapy; mOS was longer in patients who achieved a CR than in those without CR; 14/16 patients in CR achieved complete MRD response; the median duration of complete MRD response was 9.7 months.9

The efficacy of Blinatumomab retreatment after relapse was evaluated. Thus, Topp et al. evaluated 11 B-ALL patients who received Blinatumomab retreatment after initial response and relapse. 4/11 patients responded to the retreatment with a mOS of 9.4 months.10 Grade ≥3 neurologic events were observed in 3 patients.10 These observations suggest that Blinatumomab retreatment may represent a reasonable treatment for relapse in patients who have responded initially to Blinatumomab.

In the pediatric setting, Locatelli and coworkers reported the results observed on 110 R/R pediatric B-ALL patients treated with 5 cycles of Blinatumomab, showing a good safety profile with a low incidence of grade 3 or 4 of cytokine release syndrome and adverse neurologic events; a response rate not affected by the presence of adverse cytogenetic/molecular abnormalities; mOS was significantly better for patients achieving a CR with MRD negative status compared to those who remained MRD-positive (not estimable vs 9.3 months, respectively); the 1-year probability was significantly better for patients who received aHSCT after Blinatumomab compared to those without aHSCT.11

In a phase III randomized clinical trial, pediatric high-risk, first-relapse B-ALL patients received Blinatumomab as consolidation therapy, administered before allo-HSCT, resulting in improved EFS and MRD remission rate compared to chemotherapy, with EFS benefit being observed in all subgroups of patients, including those with extramedullary disease and very early relapse (<18 months).12 A longer follow-up of these patients showed a markedly better OS among patients treated with Blinatumomab compared to chemotherapy, independently of the MRD status before treatment.13

The Children’s Oncology Group ALL 1331 phase III trial compared the survival of patients with low-risk first-relapse of B-ALL treated with chemotherapy alone or chemotherapy plus Blinatumomab.14 For children, adolescents, and young adults with B-ALL in first relapse, there was no statistically significant difference in DFS and OS between the Blinatumomab and standard chemotherapy arms in an analysis performed considering the whole population of patients enrolled in the study. However, when the analysis was restricted to patients relapsing either at the level of bone marrow with or without extramedullary disease, a significant improvement in mOS was observed in the group of patients treated with Blinatumomab compared to chemotherapy alone (4-year OS rate 97.1% vs 84.8%, respectively).14

Inotozumab ozogamicin is an antibody anti-CD22-drug conjugate approved for the treatment of R/R B-ALL. A recent study showed that Inotuzumab, as well as Blinotumomab, may be used for clearing MRD in patients with B-ALL in remission after induction chemotherapy.15 However, a part of patients treated with Inotuzumab or with Blinatumomab relapsed, and there is a rationale to treat these patients with both these two antibodies. Concerning R/R B-ALL patients, Fracchiolla and coworkers reported the study of 71 patients treated for different relapses with Blinatumomab and Inotuzumab; Blinatumomab represented the first treatment for 54 patients and Inotuzumab for 14 patients.16 In the Blinatumomab/Inotuzumab group, after Blinatumomab, 65% of patients achieved a CR, with 42% of MRD negativity; in the Inotuzumab/Blinatumomab after Inotuzumab, 93% achieved a CR, with 46% of MRD negativity.16

A recent study by Jabbour et al. demonstrated that subcutaneous Blinatumomab displayed an efficacy comparable to that observed in studies involving intravenous Blinatumomab administration.17 In this study, 29 R/R B-ALL patients were treated with two different schedules of subcutaneous Blinatumomab: using two cycles of subcutaneous Blinatumomab at 250–500 ug dose, 85% of patients achieved a CR, including 75% with MRD-negativity; Blinatumomab at 500–1000 ug dose, 92%% of patients achieved a CR, including 100% with MRD-negativity.17 No treatment-related grade 4 CRS or neurologic events were reported.

In the study from Queudeville et al., through the analysis of five different trials involving the treatment of both adult and pediatric R/R B-ALL patients, patients were subdivided into two groups according to the number of bone marrow leukemic blasts (<50% and >50%). The proportion of patients achieving MRD negativity was significantly higher in patients with baseline lower tumor burden (<50% bBMB). OS and RFS were also significantly higher among patients with baseline lower leukemic burden (Table 1).18 Adverse events related to grade 3 or more CRS are more frequent among patients with higher tumor burden (Table 1). In conclusion, a high leukemia burden before therapy limits the efficacy of Blinatumomab and lowering leukemic blast levels by <50% before starting Blinatumomab therapy is required to improve its efficacy.

The treatment of patients who are resistant or relapse after Blinatumomab therapy is a great challenge. One possible salvage therapy for these patients is represented by anti-CD19 CAR-T cells. Several studies have explored the sensitivity of these refractory/relapsing patients to CD19 CAR-T cells. An initial study by Pillai et al. based on the retrospective analysis of 166 patients who have undergone CD19-directed CAR-T cell therapy showed that prior therapy with Blinatumumab, observed in a part of these patients, was associated with a higher rate of failure to achieve MRD negativity or subsequent relapse with antigen escape.19 A subgroup analysis performed in the context of the phase II ZUMA-3 trial involving the treatment of R/R B-ALL patients with CD19 CAR-T cells (Brexucabtagene autocel) showed in patients, who had prior Blinatumomab treatment, an overall CR of 60% compared to 80% observed in the patients without prior Blinatumomab.20

Myers and coworkers have performed a retrospective study on 420 pediatric B-ALL patients who received CD19-CART cells (mostly Tisagenglecleucel for R/R B-ALL); CR rates, EFS, RFS and OS, were comparable in blinatumomab-naïve (BLN) and blinatumomab-exposed patients who responded to Blinatumomab (BLR), thus indicating that Blinatumomab treatment does not preclude a response to CD19-CAR-T; however, CR, RFS, EFS and OS were reduced in blinatumomab-exposed patients who did not respond or did not achieve a CR following Blinatumomab treatment (BLNR).21 An additional exploration of these patients showed that prior Blinatumomab nonresponse was associated with an increased frequency of CD19-negative relapses after CD19 CAR-T cell therapy.22

Gupta et al. have explored 157 R/R B-ALL adult patients treated with autologous CD19-directed Brexu-Cel (CAR-T cells); 88 of them received Blinatumomab prior to CAR-T cell therapy: 70% of these patients initially responded to Blinatumomab but then relapsed (BLR) and 30% did not respond to Blinatumomab (BLNR); the rest of patients was Blinatumomab-naïve (BLNV).23 Rates of CR to CAR-T cell therapy were similar following therapy among BLR, BLNR and BLNV patients.23 However, the 1-year OS was significantly better in BLNV and BLR compared to BLNR.23 Furthermore, PFS was significantly higher in the BLNV group compared to BLR and BLNR.23

These observations, which need to be confirmed in larger, prospective clinical trials, support the conclusion that (i) CD19-targeted CAR-T cells represent an effective therapy for patients relapsing after an initial response to Blinatumomab; B-ALL patients who did not respond to Blinatumomab display shorter overall survival following CD19 CAR-T cell therapy compared to those who responded or did not receive Blinatumomab.

The possible therapeutic options for R/R B-ALL patients involving Blinatumomab are shown in Figure 1.

Blinatumomab for B-ALL in Remission MDR-Positive

Monitoring measurable residual disease (MRD) is a standardized and universally accepted method for measuring disease status in B-ALL patients, and it has become part of diagnostic patient care. MRD is a key independent predictor of the risk of relapse and long-term survival in both pediatric and adult B-ALL..24 For virtually all B-ALL patients, it is possible to evaluate MRD, either using multi-colour flow cytometry (MCFC), quantitative polymerase chain reaction (PCR) to detect immunoglobulin gene rearrangements or specific fusion transcripts, and more recently, next-generation sequencing (NGS).24 NGS is associated with high sensitivity and allows the detection of very low MRD levels (<10−4).24

A first pilot study from the GMALL group evaluated whether Blinatumomab monotherapy could improve leukaemia-free survival in B-ALL patients with MRD persistence after induction and consolidation therapy.24 20% of patients were enrolled in the study, and 80% of them displayed a conversion from MRD positivity to MRD negativity.20 In most patients, MRD negativity was achieved after 1 cycle of Blinatumomab. The probability of relapse-free survival was 78% at a median follow-up of 405 days.25 In a single-arm study, after treatment with Blinatumomab in a population of 116 adult B-ALL patients predominantly Ph-negative, with MRD-positive (≥10−3) disease, the median OS and RFS were significantly longer among patients achieving a complete MRD response, compared to those who remained MRD-positive (Table 2).26 After a longer follow-up, mOS in all patients was 36.5 months, and it was not reached in MDR-negative patients, compared to 16.5 months in MDR-positive patients.27 The 5-year survival showed a 43% survival for the whole population of patients and 50% for those achieving MRD negativity. Future studies will be required to identify patients who may benefit from Blinatumomab without HSCT, including older patients and those without a related or matched donor, and to identify therapeutic strategies that could improve outcomes further.

In another study, Gokbuget et al. evaluated the prognostic impact of MRD status after Blinatumomab treatment in 90 R/R B-ALL patients achieving a CR: patients with a CR and MRD negative status displayed a significantly longer OS and RFS compared to those with MRD positivity.28 This study supported the predictive value of MRD evaluation in B-ALL patients treated with Blinatumomab.

In a phase II study, Jabbour et al. evaluated 37 B-ALL patients (27 in first complete remission and 10 in second complete remission) in CR with MRD-positive status (≥10−4) and then treated with Blinatumomab: 73% of these patients achieved an MRD-negative remission.29 Importantly, the 3-year RFS and OS rates were 51% and 61% in patients with baseline MRD≥10−3 and 83% and 77% in patients with baseline MRD<10−3 (Table 2).29

Based on these studies, the FDA granted accelerated approval and final approval for Blinatumomab in 2018 and 2023 for the treatment of adults and children with B-ALL in first or second complete remission with MRD greater than or equal to 0.1%.

Cabanes-Hamy et al. retrospectively evaluated 73 patients who received treatment with Blinatumomab either in the first CR with MRD positivity or at relapse; high pre-Blinatumomab MDR levels were associated with shorter RFS and OS.30 In relapsed patients, those who directly received Blinatumomab had shorter RFS and OS than patients bridged to Blinatumumab after chemotherapy treatment.30

Two other retrospective studies have further supported the efficacy of Blinatumomab in MRD-positive B-ALL patients. In the NEUF retrospective observational study, 109 adult MRD-positive B-ALL patients were included (83 Ph− and 26 Ph+); in this group of patients, within the first cycle of Blinatumomab treatment, 93% of Ph− and 64% of Ph+ patients achieved an MRD response (MRD<0.01%).7

A recent real-world study reported the outcome of adult patients who received Blinatumomab in first or second complete remission.26 Patients in CR1 received Blinatumomab mostly for MRD persistence or for the inability to receive standard consolidation therapy. A complete MRD response was achieved after one Blinatumomab cycle in 83% of CR1 and 86% of CR2; after a median follow-up of 3.1 years, the 3-yr cumulative incidence of relapse was 23% for CR1 and 26% for CR2.31

Blinatumomab in B-ALL Patients in Remission MRD-Negative

Patients with newly diagnosed B-ALL frequently relapse even when achieving complete remission and MRD negativity after chemotherapy treatment. Litzow et al. have explored a group of 220 B-ALL patients achieving CR with MRD negativity (defined as MFC-MRD <0.01%) after induction chemotherapy; these patients were randomized either to receive consolidation therapy based on chemotherapy alone or chemotherapy plus Blinatumomab.32 Patients undergoing consolidation therapy plus Blinatumomab displayed a mOS significantly lower than those treated with chemotherapy alone.32 The benefit deriving from Blinatumomab administration was more pronounced in patients <55 years, and the improvement of OS induced by Blinatumomab was observed both in the group of patients MRD-negative and those with MRD levels between undetectable and 0.01%.28 The RFS in MRD-negative patients favored the Blinatumomab arm vs the chemotherapy arm.33 Another subgroup analysis of these patients showed that the OS of patients who received 1–2 cycles of Blinatumomab displayed no significant difference compared with the controls.34

Gu and coworkers have explored the effectiveness of Blinatumomab in clearing NGS-measurable MRD in pediatric B-ALL patients.35 To this end, 19 B-ALL pediatric patients, bearing at least one unfavorable genetic abnormality, such as KMT2A rearrangement, in hematological CR with MRD <10−4 after induction or consolidation chemotherapy; however, all these patients were identified as MRD-positive by NGS.35 After Blinatumomab treatment, MRD negativity by MFC was 95%, and the NGS-MRD negativity rate at 10−6 was 68%.37

The possible therapeutic options involving Blinatumomab for patients achieving a CR after induction chemotherapy with either MRD-positive or MRD-negative condition are shown in Figure 2.

Blinatumomab and Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (a-HSCT) represents a potentially curative approach for B-ALL patients, as well as for other hematologic malignancies. However, a significant proportion of B-ALL patients relapses after a-HSCT. These relapsing patients have a poor prognosis, and some studies have evaluated their response to Blinatumomab. Stein et al. evaluated the response of 64 B-ALL patients who relapsed after aHSCT and investigated the safety and efficacy of Blinatumomab.36 45% of these patients achieved a CR within two cycles of Blinatumomab treatment and 30% with a complete MRD response.33 These observations have supported Blinatumomab as a valuable salvage therapy in relapsing B-ALL patients after aHSCT.36

Gaballa and coworkers have reported the result of a single center phase II study evaluating the administration of Blinatumomab during the first year after a-HSCT, with the main aim to mitigate relapse in high-risk B-ALL patients.39 A comparison with a contemporary group of 57 B-ALL patients suggests no benefit from Blinatumomab administration.39 Correlative studies suggested the classification of patients into responders and non-responders according to specific T-cell profiles.37 It is important to note that in this study, B-ALL patients remained on immunosuppression during Blinatumomab treatment.37 A more recent phase Ib/II trial evaluated the tolerability and the efficacy of Blinatumomab as post-aHSCT remission maintenance in B-ALL (19 patients) and NHL patients off immunosuppression.38 The results showed that post-aHSCT maintenance therapy is feasible with minimal toxicity in patients off immunosuppression with 18% of relapses, all occurring at the level of the central nervous system.38

Chauvet et al. evaluated 72 B-ALL patients relapsing after aHSCT: 50 patients received Blinatumomab alone, and 22 patients received Blinatumomab plus donor lymphocyte infusion (DFI).39 Two-year OS was not significantly different between these two groups of patients; PFS and adverse events were similar in the two groups of patients.39 The observations suggest that the DLI with Blinatumomab administration to B-ALL patients relapsing after aHSCT is safe but does not seem to improve outcomes.

Other studies have evaluated the administration of Blinatumomab pre-transplantation. There is a strong rationale for using Blinatumomab before aHSCT as a tool to clear MRD. In fact, residual MRD before HSCT is predictive of recurrence and thus, achieving MRD negativity before HSCT is a key strategy to improve and optimize the curative capacity of transplantation. Two randomized, phase III trials have shown the superiority of Blinatumomab compared to conventional chemotherapy as a consolidation treatment before aHSCT in pediatric patients with high-risk or intermediate-risk B-ALL, showing an improved disease-free survival, lower incidence of disease relapse post-HSCT and significantly reduced toxicity.12,40 Furthermore, a post-hoc analysis of the study of Locatelli et al.12 showed that a higher proportion of patients with high-risk first-relapse B-ALL with MRD positivity at the time of randomization achieved an MRD negative status after treatment with Blinatumomab compared with patients treated with intensive chemotherapy.43 OS showed a strong benefit with Blinatumomab vs chemotherapy. Furthermore, Blinatumomab also improved outcomes for patients who had already achieved an MRD-negative condition prior to randomization.41

Sayyed and coworkers have explored 177 adult B-ALL patients undergoing aHSCT: 26.5% of these patients received Blinatumomab before HSCT, while the rest of the patients received chemotherapy.42 Pretransplant Blinatumomab has been associated with improved OS and lower risk of non-relapse mortality in B-ALL patients undergoing HSCT, seemingly reflecting a lower burden of treatment-related toxicity in the Blinatumomab-treated population.42 Multivariate analysis confirmed the association between pretransplant Blinatumomab and improved OS and NRM.44 A similar study was performed on pediatric B-ALLs.43

Blinatumomab is Used in the Frontline Treatment of Philadelphia-Positive B-ALL

, the most frequent cytogenetic abnormality in adult B-ALL. Several recent studies have shown that it is possible to replace the chemotherapy backbone with Blinatumomab in association with TKIs.

In the LAL 0216 (D-ALBA) trial, the GIMEMA group explored the safety and efficacy of a chemotherapy-free regimen based on Blinatumomab plus Dasatinib in newly diagnosed Ph+ B-ALL patients (Table 3 and Figure 3).46 In this study, 63 newly diagnosed B-ALL patients were treated first with an induction therapy based on Dasatinib plus glucocorticoids and then with two to five cycles of Blinatumomab and Dasatinib and 12 doses of intrathecal chemotherapy.44 In an initial report of this study, at a median follow-up of 18 months, OS was 95% and DFS 88%.44 Patients with IKZF1 deletion plus additional genetic abnormalities displayed a lower rate of DFS compared to patients without these genetic aberrations.44 A recent update of the study reported the long-term results of this study with a median follow-up of 53 months.45 After induction therapy, there was a difference in DFS and OS between patients with MRD-positivity and MDR-negativity. However, after two cycles of Blinatumomab, no significant differences in DFS and OS between molecular and nonmolecular responders were observed, thus suggesting that Blinatumomab is effective in preventing a relapse also in patients with MRD-positive disease after induction therapy.47 Patients with MRD-positivity received an aHSCT.45 These observations support the capacity of a chemotherapyfree regimen based on Dasatinib and Blinatumomab to induce durable long-term hematologic and molecular responses in adult Ph+ B-ALL patients.45

Advani and coworkers have reported the results of a clinical trial carried out in 24 older (65 years of age or older) Ph+ B-ALL with newly diagnosed disease or R/R disease, treated with induction therapy based on Dasatinib/Prednisone: patients achieving a CR continued this treatment up to day 84, while those not achieving a CR after day 56 attempted a re-induction treatment plus one cycle of Blinatumomab, followed by 3 cycles of post-remission therapy based on Blinatumomab and Dasatinib and maintenance therapy always based these two drugs (Table 3).46 This study showed that this therapeutic regimen was safe and feasible.46

A phase II study designed Blinatumomab as a chemotherapy-sparing strategy in patients with Ph+ B-ALL (BLISSPHALL). For patients in CR, Blinatumomab was used as early as 6 weeks into treatment, with the aim of accelerating MRD clearance and suppressing resistant clones early in the disease course. A maintenance phase based on Blinatumomab plus Dasatinib was included for patients in molecular complete response (CMR).48 A strategy to suppress T315I clones and reduce their recurrence in the CNS could be achieved by combining third-generation TKIs or chemotherapy with Blinatumomab.

A single-centre, single-arm, phase II study enrolled 60 B-ALL patients with newly diagnosed or R/R B-ALL or chronic myeloid leukemia in the lymphoid blast phase and received treatment with the combined administration of Ponatinib and Blinatumomab for up to five cycles of treatment.49 (Table 3 and Figure 3) With a median follow-up of 16 months, 87% of patients with newly diagnosed B-ALL had a complete molecular response, and 79% of patients with R/R Ph+ B-ALL had a complete molecular response.49 In an updated analysis, 62 patients with newly diagnosed B-ALL were included, of whom 55 patients were available for molecular response; 84% achieved a complete molecular response; the 2-year OS was 89%, and EFS was 77%.50

In the GIMEMA ALL2820, whose preliminary results were recently reported, Dasatinib was replaced by Ponatinib, which was administered for 70 days together with steroids, followed by 2 cycles of Blinatumomab consolidation and 15 doses of intrathecal chemotherapy.51 The maintenance therapy consisted either of Ponatinib or aHSCT for MRD-positive or IKZF1plus patients. At the end of the induction therapy, 95% of patients achieved complete hematological remission; with a median follow-up of 6.1 months, only one relapse was observed (IKZF1plus with T315I mutation).51

Olvermbatinib is a novel third-generation TKI that has been demonstrated to effectively target a wide range of BCR-ABL1 kinase mutations, particularly T315I, in CML patients and B-ALL patients.52 Olvermbatinib, in association with chemotherapy53 or with Blinatumomab,52,54 was active in treating B-ALL patients who have failed TKI-based regimens, including T315I-mutated cases. Zhang et al. have reported the results on the treatment of 13 B-ALL patients (11 Ph+ and 2 Ph-like) with Olvermbatinib and Blinatumomab for one cycle of treatment (both administered during the induction phase), with 72.7% of patients achieving a CMR.55

The combination of Ponatinib with hyper-CVAD chemotherapy resulted in high rates of complete molecular remission and survival.56 A recent phase II study explored in Ph+ B-ALL patients the safety and the efficacy of a therapeutic regimen based on the sequential combination of low-intensity chemotherapy mini-Hyper-CVD and Ponatinib followed by Blinatumomab and Ponatinib.45 Twenty patients were enrolled in this study, including 12 newly diagnosed B-ALL, 4 R/R B-ALL, and 4 lymphoid crises of CML. A high rate of complete molecular remission was observed.57 With a median follow-up of 25 months, the rates of 2-year remission duration and OS in the newly diagnosed cohort were 90% and 82%, respectively.57

Schwartz et al. have reported the first results of a phase II clinical study involving the evaluation of consolidation with Ponatinib and sequential Blinatumomab and Chemotherapy after low-intensity Dasatinib-based induction in patients with newly diagnosed B-ALL (Figure 3).58 14 patients received initial induction treatment with Dasatinib plus prednisone until CMR was achieved; this treatment was followed by up to four cycles of consolidative chemotherapy (high-dose methotrexate and intermediate-dose cytarabine) plus Ponatinib and Blinatumomab; patients not proceeding to aHSCT continue Ponatinib monotherapy up to 5 years and 12 doses in intrathecal chemotherapy.58 21% of the patients underwent aHSCT at CR1. The results obtained in this study were compared to those observed in a historical group of patients treated in the same institution with Dasatinib induction treatment and aHSCT, and they showed a better RFS rate and a comparable OS rate.58

The studies on therapy of newly diagnosed Ph+ B-ALL patients with either Dasatinib plus Blinatumomab or Ponatinib plus Blinatumomab indicate that these patients could be spared the toxicities associated with chemotherapy and the need for aHSCT in first response.

Blinatumomab in Frontline Treatment of Philadelphia-Negative B-ALL Patients

The outcome of adult B-ALL patients with Ph-negative B-ALL markedly improved following the introduction therapy of a chemotherapy regimen inspired by pediatric protocols associated with the evaluation of MRD at various time points during treatment, thus allowing a rational stratification of each patient or aHSCT, if required.

This treatment strategy inspired the phase II GIMEMA LAL2317 trial, and the study evaluated whether the introduction of Blinatumomab may improve the rate of patients achieving an MRD-negative status (Table 3).59 In this study, adult Ph-negative B-ALL patients were treated with a pediatric chemotherapy backbone, with the introduction of two treatments with Blinatumomab after early consolidation cycle 3 and late consolidation cycle 6.46 One hundred forty-nine patients were enrolled in this study. At the end of the induction period, 88% of patients achieved a CR, with a pronounced difference according to the age of the patients.59 After early consolidation, 70% achieved an MRD-negative condition; the rate of MRD negativity increased to 93% after the first cycle of Blinatumomab treatment.59 The OS was significantly better for patients achieving MRD-negativity. The cumulative incidence of relapse was 27.5%.59 For patients achieving MRDnegativity, the cumulative incidence of relapse was 42.5% in Ph-like cases, compared to 17.5% in the remaining patients.59 Factors affecting OS were the age of patients, CR achievement and MRD status observed after the first cycle of Blinatumomab.59–60

The GRAAL-2014-Quest study evaluated Blinatumomab in first-line in B-ALL defined as highrisk for one of these three conditions, including KMT2A rearrangements, IKZF1 intragenic deletion or MRD-positivity post-induction.61 High-risk B-ALL patients responding to induction treatment were enrolled in this study: patients with an aHSCT indication and a stem cell source received Blinatumomab until transplant for a minimum of 4 weeks; these patients received Blinatumomab during consolidation and maintenance therapy (Table 3).61 MRD response was lower in patients with high pre-Blinatumomab MRD levels, while not impacted by age, WBC, or oncogenic subgroup; with a median of 20 months, 18-month DFS and OS were 78.8% and 92.1%, respectively.61 Patients with a very high-risk condition (i.e., MRD <0.1% at 6 weeks or <0.01% at 12 weeks) displayed a worse DFS.61 After an amendment, the modified study GRAALL-2014/B study included a group of patients receiving, when in remission with MRD>10−3 (or with >10−4 post-consolidation) Blinatumomab and a group of control patients undergoing only chemotherapy treatment as consolidation therapy (Table 3).62 The median age of these patients was 34 years; 17% of them bear KMT2A rearrangements, and 40% have IKZF1 deletion. Patients treated with Blinatumomab achieved a rate of MRD negativity higher than patients treated with chemotherapy alone.62 A sub-analysis of this study showed that among high-risk B-ALL Ph-negative patients who benefit from Blinatumomab, there is a consistently heterogeneous landscape of response among genetic entities, with patients with IKZF1 deletion exhibiting the most significant benefit from Blinatumomab of DFS.63

Several studies have associated the early use of Blinatumomab with a reduction of chemotherapy intensity and burden. A phase II Australian Leukemia and Lymphoma Group (ALLG) evaluated reduced-intensity chemotherapy in combination with Blinatumomab. Thirty patients received debulking low-intensity chemotherapy with cyclophosphamide, vincristine and dexamethasone, followed by 7 days of Blinatumomab; the patients then received three alternating cycles of Blinatumomab and part B cycles of hyper-CAVD, followed by two years of maintenance therapy in patients and proceeding to aHSCT.64 All treated patients achieved a CR.64 4 patients proceeded to aHSCT. The results appeared encouraging for older patients.64

The ALLG study group developed a trial to evaluate Blinatumomab in sequence with chemotherapy in a population of older, newly diagnosed B-ALL patients; in this study, Blinatumomab replaced three cycles of standard consolidation therapy.65 Overall, the tolerability and efficacy of this regimen were very promising, with a high rate of hematologic and molecular responses.53 In comparison with the current standard therapy, the MRD response rates were significantly better, and OS was superior to standard treatment.65

The multicentre, single-arm, phase II trial (NCT055557110) enrolled adult patients (15–59 years) with newly diagnosed Ph-negative B-ALL; the induction regimen comprised reduced-intensity chemotherapy, followed by two weeks of Blinatumomab.54 The MRD negativity rate was 90.5% after 2 weeks of Blinatumomab.66 Adverse events were rare, with 1/21 patients exhibiting grade 3 CRS and no patient displaying grade 3 or more neurologic events.66

A phase II study explored in 75 newly diagnosed Ph− B-ALL patients the safety and the efficacy of a therapeutic regimen based on hyperCVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of Blinatumomab at standard doses, in 37 patients Inotuzumab was added to 2 cycles of MTX/Ara-C.55 In the whole population of patients (38 treated with HCVAD+Blina and 37 with HCVAD+Ino+Blina), the 3-yr OS was 88% and RFS 89%; the 3-year OS rate for patients without or with high-risk features was 93% and 83%, respectively.67

Two recent studies have explored the use of Blinatumomab in newly diagnosed pediatric B-ALL patients. In this context, van der Sluis and coworkers have evaluated the safety and the efficacy of Blinatumomab added to induction chemotherapy in 30 infants affected by KMT2A-rearranged B-ALLs. All 30 patients received the full course of Blinatumomab. 28/30 (93%) patients displayed either MRD-negativity (16 patients) or very low MRD levels (<5x10−4) (12 patients) after Blinatumomab infusion. Two-year DFS and OS were 81.6 and 93.3% in this study and compared very favorably with the corresponding rates observed in the Interinfant-06 study based on chemotherapy alone.68 In conclusion, this study showed that Blinatumomab added to the chemotherapy backbone used in the study Interinfant-o6 appeared to be safe and displayed high efficacy compared with historical controls.68

Schrappe and coworkers reported data on the safety profile of pediatric patients with high-risk B-ALL in first complete remission; after a 4-drug induction phase and two weeks of consolidation treatment, the patients were randomized to receive either two additional courses of consolidation chemotherapy or two 28-day courses of Blinatumomab.69 The toxicity profile of Blinatumomab was more favorable to the intensive chemotherapy approach.69 Outcome data are expected to demonstrate that the Blinatumomab arm is not inferior to chemotherapy.

Conclusions

The introduction of the bispecific CD19-CD3 antibody Blinatumomab in the treatment of B-ALL patients has significantly improved their outcomes, particularly those of adult B-ALL patients.

Studies carried out in R/R B-ALL patients in combination with chemotherapy improve RFS and OS and increase the frequency of patients who underwent an HSCT when in complete remission. Future studies will be required to define therapeutic strategies, such as a decrease of tumor burden before immunotherapy, to increase the number of patients responding to Blinatumomab. Importantly, patients relapsing after an initial response to Blinatumomab are clearly responsive to CD19 CAR-T treatment, while patients refractory to a previous Blinatumomab treatment are less responsive to CAR-T cells. Ongoing studies are evaluating the capacity of other drugs, such as Inotuzumab or ICIs, that, in combination with Blinatumomab, could improve its efficacy in R/R B-ALL patients.

Other studies have shown that Blinatumomab could represent an efficient therapeutic tool for clearing residual disease in B-ALL patients achieving a CR after induction chemotherapy with an MRD. In line with these observations, several studies have shown that there is a strong rationale for using Blinatumomab as a consolidation treatment before aHSCT. The consolidation therapy pre-transplantation with Blinatumomab improves RFS and OS compared to consolidation therapy based on chemotherapy only.

Several studies have explored the use of Blinatumomab in the first line of treatment for newly diagnosed Ph+ or Ph− B-ALL patients. The introduction of Blinatumomab in the first-line treatment of Ph+ patients allowed to develop a chemotherapy-free approach based on the combination of Blinatumomab with a TKI (either Dasatinib or Ponatinib), resulting in high rates of complete molecular responses and long-term survival; the use of Ponatinib or other third-generation TKIs seems to reduce the rate of relapses related to generation/selection of resistant ABL1 mutations. These studies have shown that these chemotherapy-free treatments can spare the toxicities related to chemotherapy and reduce the need for aHSCT. The clinical studies carried out in newly diagnosed Ph− B-ALL patients showed a benefit of adding Blinatumomab, as supported by the achievement of high rates of MRD negativity, OS and DFS, better than those observed in historical controls. Future randomized clinical studies will be required to demonstrate the real improvement related to the addition of Blinatumomab to the chemotherapy treatment of Ph− newly diagnosed B-ALL.

Figure 1 Therapeutic options for patients with R/R B-ALL involving first treatment with Blinatumomab: patients responding to this treatment and achieving a CR with MRD-positivity may underwent allo-HSCT or CAR-T cell therapy; patients resistant or relapsing after Blinatumomab treatment may be either retreated with Blinatumumab and patients responding to this salvage treatment may be allo-transplanted or treated with CD19 CAR-T cells and then with allo-HSCT.

Figure 2 Therapeutic options for newly diagnosed B-ALL patients achieving a CR following induction and consolidation chemotherapy, with MRD-positive or MRD-negative disease are outlined.

Figure 3 Outline of the main clinical trials involving the treatment of newly diagnosed Philadelphia-positive with Blinatumomab. From the top to the bottom: top pane shows the outline of the chemotherapy-free GIMEMA LAL 2116 trial by Foà et al.;44–45 middle panel shows the outline of the chemotherapy-free clinical trial NCT 03263572 trial by Jabbour et al.;49–50 bottom panel shows the outline of the clinical trial by Schwartz based on Blinatumomab and chemotherapy by Schwartz et al.58

Table 1 Main clinical trials evaluating the safety and the efficacy of Blinatumomab in adult and pediatric R/R B-ALL.

Study	Blinatumomab design	Number of patients	Median age (years) (range)	CR rate %	MRD negativity	Overall Survival	EFS RFS DFS	CRS % NE %	
TOWER, phase III, randomised4	R/R B-ALL patients randomised to chemotherapy or Blinatumomab	405 (total)
134 (chemo)
271 (Blina)	41 (18–80)	16 (chemo)
34 (Blina)	In patients in CR:
48% (chemo)
76% (Blina)	4.0 mo (chemo)
7.7 mo (Blina)	EFS:
4.6 mo (chemo)
7.7 (Blina)	CRS:
0 (chemo)
4.9 (Blina)
NE:
8.3 (chemo)
9.4 (Blina)	
Pooled analysis of 5 different trials18	R/R B-ALL	683
166(pediatric)
517(adult)	33
Pediatric
8.3 (0–17)
Adult
41 (18–80)	Pediatric <50%
bBMB 65% >50%
bBMB 38%
Adult <50%
bBMB 69% >50%
bBMB 34%	Pediatric
<50% bBMB 51%
>50% bBMB 25%
Adult
<50% bBMB 54%
>50% bBMB 27%	Pediatric
<50% bBMB 48%
>50% bBMB 32%
Adult
<50% bBMB 33%
>50% bBMB 21%	EFS
Adult <50%
bBMB 20% >50%
bBMB 10%	CRS <50%
bBMB 1% >50%
bBMB 4%
NE <50%
bBMB 7.6% >50%
bBMB 8.2%	
Phase III randomized clinical trial 2012021512,13	Open-label phase III trial in Ph− patients, high-risk, first relapse post-induction and two consolidation cycles, MRD-positive	104 Randomized to receive chemotherapy or Blinatumomab 57 Chemo 54 Blino	5.5 (1–17)	NR	54% Chemo
90% Blina	4-yr OS
27% Chemo
59% Blina	4-yr EFS 43%
Chemo 69% Blina	CRS
2%
(Chemo) 5.6%
(Blina)
NE 2%
(Chemo) 3.7% (Blina)	
RIALTO Phase II11	R/R B-ALL patients received up to 5 cycles of Blinatumomab	110	8.5 (0.4–17)	52%	52%	14.6 months
MDR− NE
MDR+ 9.3 m	RFS
8 months
MDR− 8 m
MDR+ 2.8 m	CRS 1.8%
NE 3.6%	
ALL1331 Phase III14	Low-risk B-ALL treated with chemo alone or chemo plus Blinatumomab	255
174 BM±EM
81 IEM	(1–30)
10 Chemo
11 Blina	NR	NR	4-yr OS
Blin 90.4%
Chemo 79.6%
Blin 97%
Chemo 72%
Blina 76%
Chemo 68%	4-yr DFS
Blin 61.2 %
Chemo 49.5%
Blin 84%
Chemo 53%
Blina 36%
Chemo 38%	CRS 3% (Blina)
NE 5% (Blina)	

Table 2 Clinical trials exploring the safety and the efficacy of Blinatumomab in MRD-positive B-ALL patients at first or later CR.

Study	Blinatumomab design	Number of patients	Median age (years) (range)	MRD Negativity	Overall Survival	EFS RFS DFS	CRS % NE %	HSCT	
BLAST, phase II26,27	Single-arm, open-label to evaluate safety and efficacy of Blinatumomab in adult B-ALL patients in CR with MRD≥10−3	116 (total)
64% CR1
34% CR2
2% CR3
96% Ph−	45 (18–76)	78% (after first cycle) 80% (after second cycle)	After a follow-up of 59.8 months mOS 36.5 mo MRD− NR MRD+ 16.5 mo Patients in CR1 41.2 mo Patients in CR 2 23.1 mo	After a follow-up of 29.9 months
mPFS 18.9 mo
MRD− 23.6 mo
MRD+ 5.7 mo
Patients in CR1 14.6 mo
Patients in CR2 5.7 mo	NE 9% (first cycle)
3% (second cycle)	CRS:
0 (chemo)
4.9 (Blina)
NE:
8.3 (chemo)
9.4 (Blina)	
Phase II29	Prospective single-arm phase II study with adult B-ALL, MRD >10−4 after first or later CR	37
73% CR1
27% CR2,3
53% Ph−
47% Ph+	43 (22–84)	65% (after the first cycle) 80% (after the second cycle)	3-year OS
MRD− 72%
MRD+ 52%
CR1 72%
CR2 51%
aHSCT 71%
No-AHSCT 66%	3-year RFS
MRD− 66%
MRD+ 52%
CR1 68%
CR2 37%
aHSCT 71%
No-aHSCT 58%	CRS 3%
NE 8%	41% allo-HSCT 10/15 with allo-HSCT surviving 12/18 without allo-HSCT and responding to Blinatumomab, surviving	
Real-world study GRAALL group30	Retrospective analysis on B-ALL patients with CR, MRD-positive	35 MRD level >1% 28% 0.1–1% 30% 0.01–0.1% 28% <0.01% 14%	32 (17–74)	89%	mOS not reached
3–yr OS
>1% 33%
0.1–1% 58%
<0.1% 86%	mRF not reached 3-yr PFS
>1% 33%
0.1–1% 58%
<0.1% 78%	Not reported	66% allo-HSCT	

Table 3 Clinical trials exploring the safety and the efficacy of Blinatumomab in newly diagnosed B-ALL patients, Ph+ or Ph−.

Study	Blinatumomab design	Number of patients	Median age (years) (range)	CR rate	MRD Negativity	Overall Survival	EFS RFS DFS	HSCT	
GIMEMA LAL 2116 D-ALBA Phase II44–45	ND Ph+ B-ALL Dasatinib induction for 85 days and then 2–5 cycles of therapy with Blinatumomab plus Dasatinib	63 newly diagnosed Ph+ B-ALL	54 (24–82)	98%	Ater induction 29%
After consolid. 60%	4-year 80.7%
Patients with IKZF1plus have shorter OS	4-year
DFS : 75.8%
EFS : 74.6%	39%	
Phase II NCT 0214341446–47	Dasatinib and Prednisone as induction therapy followed by Blinatumomab and Dasatinib for 3 cycles, followed by Dasatinib/Prednisone maintenance	24 newly diagnosed Ph+ B-ALL	73 (65–87)	88% (after induction therapy) 95% (after Blinatumomab)	63% by RT-PCR	3-year OS 87% mOS 6.5 years	3-year EFS 77% mDFS not reached	Not compatible for the age of patients	
Phase II NCT 0326357249	5 cycles of combined treatment with Ponatinib and Blinatumomab, followed by Ponatinib monotherapy.	60 40 Newly diagnosed Ph+ (ND) 14 R/R Ph+ B-ALL (R/R) 6 CML lymphoid blast phase (CML)	51 (36–68)	95% (ND)
85% (R/R)	87% (ND)
79% (R/R)
33% (CML)	2-year 89%	2-year EFS 77%	3%	
GIMEMA LAL 2317 Phase II59	Adult Ph− B-ALL patients treated with induction chemotherapy and then with six consolidation-therapy cycles; at cycles 3 and 6 Blinatumomab was added	149 12 KMT2A r 5 TCF3/PBX1 31 Ph-like	41 (18–65)	88% (after induction Ct)
18–40yr 90%
40–50yr 92%
>55yr 64%
95% (after Blinatumomab)	70% (after induction Ct)
93% (after Blinatumomab)	71% 18–40yr
76% 40–50yr
74%
>55yr 49%	DFS 66%
18–40yr 71%
40–50yr 62%
>55yr 42%
CIR 27.5%
MRD− 17.5%
Ph-like 42.5%	Not Reported	
GRAAL-2014-QUEST Phase II60	B-ALL patients in remission after induction and consolidation 1, received treatment with Blinatumomab	95 High-risk Ph− B-ALL	35 (18–60)	82%	Pre-Blina
MRD<0.01% 56%
Post-Blina
MRD<0.01% 74%	Follow-up 18 months 92%	Follow-up 18 months
DFS 78%	42%	
GRAAL-2014-QUESTB Phase II61	Blinatumomab was administered during consolidation to adult Ph− B-ALL patients and compared to a group of patients receiving only chemotherapy during consolidation	198
104
Chemotherapy
94
Blinatumomab	34 (18–59)	100% (before treatments)	After consolidation 2
72% (Blina)
76% (Chemo)	2.5 years
79% (Blina)
76% (chemo)	2.5 years DFS
72% (Blina)
54% (Chemo)
2.5 years
CIR
20% (Blina)
41% (Chemo)	47% (Blinatumomab)
37% (Chemotherapy)	

Competing interests: The authors declare no conflict of Interest.
==== Refs
References

1 Klein C Brinkmann U Reichert JM Kontermann RE The present and future of bispecific antibodies for cancer therapy Nat Rev Drug Discov 2024 10.1038/s41573-024-00896-6 38448606
2 Surowka M Klein C A pivotal decade for bispecific antibodies? MABS 2024 16 2321625 10.1080/19420862.2024.2321635 38465614
3 Bargou R Leo E Zugmaier G Klinger M Goebeler M Knop S Noppeney R Viardot A Hess G Schuler M Einsele M Tumor regression in cancer patients by very low doses of a T cell-engaging antibody Science 2008 321 974 977 10.1126/science.1158545 18703743
4 Kantarjian H Stein A Gokbuget N Fielding AK Schuh AC Ribera JM Wei A Dombret H Foa R Bassan R Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia N Engl J Med 2017 3 836 847 10.1056/NEJMoa1609783 28249141
5 Topp MS Gokbuget N Zugmaier G Stein AS Dombret H Chen Y Ribera JM Bargou RF Horst HA Kantarjian H Long-term survival of patients with relapsed/refractory acute lymphoblastic leukemia treated with Blinatumomab Cancer 2021 127 554 559 10.1002/cncr.33298 33141929
6 Topp MS Stein AS Gokbuget N Horst HA Boissel N Martinelli G Kantarjian H Bruggemann M Chen Y Zugmaier G Blinatumomab as first salvage versus second or later salvage in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia: results of a pooled analysis Cancer Med 2021 1 2601 2610 10.1002/cam4.3731 33734596
7 Boissel N Chiaretti S Papayannidis C Ribera JM Bassan R Sokolov AN Alam N Brescianini A Pezzani I Kreuzbauer G Real-world use of Blinatumomab in adult patients with B-cell acute lymphoblastic leukemia in clinical practice: results from the NEUF study Blood Cancer J 2023 13 2 10.1038/s41408-022-00766-7 36599847
8 Webster JA Luskin MR Rimando J Blackford A Zeidan AM Sharon E Stericher H DeAngelo DJ Uznik L Gojo I Blinatumomab in combination with immune checkpoint inhibitors (ICIs) of PD-1 and CTLA-4 in adult patients with relapsed/refractory (R/R) CD19 positive B-cell acute lymphoblastic leukemia (ALL): results of a phase I study Blood 2023 142 suppl1 966 10.1182/blood-2023-191109
9 Martinelli G Boissel N Chevalier Ottmann O Gokbuget N Rambaldi A Ritchie EK Papayannidis C Tuglus CA Morris JD Long-term follow-up of Blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia: final analysis of ALCANTARA study Eur J Cancer 2021 146 107 114 10.1016/j.ejca.2020.12.022 33588145
10 Topp MS Stelljes M Zugmaier G Barnette P Heffner LT Trippett T Duell J Bargou RC Holland C Benjamin JE Blinatumomab retreatment after relapse in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia Leukemia 2018 32 562 565 10.1038/leu.2017.306 28990581
11 Locatelli F Zugmaier G Mergen N Bader P Jeha S Schlegel PG Bouquin JP Handgretinger R Brethon B Rossig C Blinatumomabv in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis Blood Adv 2022 6 1004 1013 10.1182/bloodadvances.2021005579 34979020
12 Locatelli F Zugmaier G Rizzari C Morris JD Gruhn B Klingbiel T Parasole R Linderkamp C Flotho C Effect of Blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial JAMA 2021 325 843 854 10.1001/jama.2021.0987 33651091
13 Locatelli F Zugmaier G Rizzari C Morris JD Gruhn B Klingbiel T Parasole R Linderkamp C Flotho C Improved survival and MRD remission with Blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL Leukemia 2023 37 222 225 10.1038/s41375-022-01770-3 36482128
14 Hogan LE Brown PA Ji L Xu X Devidas M Bhatla T Borwitz MJ Raetz EA Carroll A Heerema NA Children’s oncology group AALL1331: phase III trial of Blinatumomab in children, adolescents, and young adults with low-risk B-cell ALL in first relapse J Clin Oncol 2023 41 4118 4129 10.1200/JCO.22.02200 37257143
15 Jabbour E Haddad PG Short NJ Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission Blood 2024 143 417 421 10.1182/blood.2023022330 37879077
16 Fracchiolla NS Sciumé M Papayannidis C Vitale A Chiaretti S Annunziata M Giglio F Salutari P Forghieri F Lazzarotto D Blinatumomab and inotuzumab ozogamicin sequential use for the treatment of relapsed/refractory acute lymphoblastic leukemia: a real-life campus A11 study Cancers 2023 15 4623 10.3390/cancers15184623 37760592
17 Jabbour E Zugmaier G Agrawal V Martinez-Sanchez P Rifon Roca J Cassaday R Boll B Rijneveld A Abdul-Hay M Huguet F Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia Am J Hematol 2024 99 586 595 10.1002/ajh.27227 38317420
18 Queudeville M Stein AS Locatelli F Ebinger M Handgretinger R Gokbuget N Gore L Zeng Y Gokani P Zugmaier G Low leukemia burden improves Blinatumomab with relapsed/refractory B-cell acute lymphoblastic leukemia Cancer 2023 129 1384 1393 10.1002/cncr.34667 36829303
19 Pillai V Muralidharan K Meng W Bagashev A Oldridge DA Rosenthal J Van Arnam J Melenhorst JJ Mohan D DiNofia AM CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy Blood Adv 2019 3 3539 3549 10.1182/bloodadvances.2019000692 31738832
20 Shah RD Cassaday RD Park JH Houot R Oluwole OO Logan AC Boissel N Leguay T Bishop MR Topp MS Subgroup analyses of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) in ZUMA-3 HemaSphere 2022 6 S3 10.1097/01.HS9.0000844312.20412.89
21 Myers RM Taraseciviute A Steinberg SM Lamble AJ Sheppard J Yates B Kovach AE Wood B Borowitz MJ Stetler-Stevenson M Blinatumomab nonresponse and high disease burden are associated with inferior outcomes after CD19-CAR for B-ALL J Clin Oncol 2022 40 932 944 10.1200/JCO.21.01405 34767461
22 Lamble AJ Myers RM Taraseviciute A John S Yates B Steinberg SM Sheppard J Kovach AE Wood B Borowitz MJ Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells Blood Adv 2023 7 575 584 10.1182/bloodadvances.2022007423 35482927
23 Gupta VK Roloff GW Muffly LS Aldoss I Kopmar NE Lin C Dekker SE Jeyakumar N O’Connor TE Zhang A Impact of prior response to Blinatumomab on outcomes of brexucabtagene autoleucel (Brexu-cel) in adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL): results from the real-world outcomes collaborative of CAR-T in adult ALL (ROCCA) Blood 2023 142 suppl 1 2119 10.1182/blood-2023-182915 37871575
24 Saygin C Cannova J Stock W Muffly L Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients Haematologica 2022 107 2783 2793 10.3324/haematol.2022.280638 36453516
25 Topp MS Kufer P Gokbuget N Goebele M Klinger M Neumann S Horst HA Raff T Viardot A Schmidt M Targeted therapy with the T-cell engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival J Clin Oncol 2011 29 2493 2498 10.1200/JCO.2010.32.7270 21576633
26 Gokbuget N Dombret H Bonifacio M Reichle A Graux C Faul C Diedrich H Topp MS Bruggemann M Horst HA Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia Blood 2018 131 1522 1531 10.1182/blood-2017-08-798322 29358182
27 Gokbuget N Zugmaier G Dombret H Stein A Bonifacio M Graux C Faul C Bruggemann M Taylor K Mergen N Curative outcomes following Blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia Leukemia & Lymphoma 2020 61 2665 2673 10.1080/10428194.2020.1780583 32619115
28 Gokbuget N Kantarjian H Bruggemann M Stein AS Bargou RC Dombret H Fielding AK Heffner L Rigal-Huguet F Litzow M Molecular response with Blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia Blood Adv 2019 3 3033 3037 10.1182/bloodadvances.2019000457 31648325
29 Jabbour EJ Short NJ Jain N Jammal N Jogersen J Wang S Ohanian M Alvarado Y Kadia T Blinatumomab is associated with favorable outcomes in patients with B-cell lineage acute lymphoblastic leukemia and positive measurable residual disease at a threshold of 10–4 and higher Am J Hematol 2022 97 1135 1141 10.1002/ajh.26634 35713551
30 Cabannes-Hamy A Brissot E Leguay T Huguet F Chevallier P Hunault M Escoffre-Barbre M Cluseau T Balsat M Nguyen S High tumor burden before Blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A realworld study by the GRAAL Haematologica 2022 107 2072 2080 10.3324/haematol.2021.280078 35263986
31 Urbino I Lengline E Rabian F Cerrano M Kim R Chevillon F Ferrero D Sebert M Dhédin N Itzykson R Blinatumomab consolidation for adult B-cell acute lymphoblastic leukemia in first and second complete remission Blood Adv 2024 in press 10.1182/bloodadvances.2023012139 38507689
32 Litzow MR Sun Z Paietta E Mattison RJ Lazarus HM Rowe JM Arber DA Mullighan CG Willman CI Zhang Y Consolidation therapy with Blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission; results from the ECOG-ACRIN E1910 randomized phase III national cooperative clinical trials network trial Blood 2022 140 suppl 1 LBA-1 10.1182/blood-2022-171751
33 Litzow M Sun Z Mattison R Paietta E Mullighan C Roberts K Zhang Y Racevskis J Willman C Wieduwilt M Consolidation with Blinatumomab improves overall and relapse-free survival in patients with newly diagnosed B-cell acute lymphoblastic leukemia: impact of age and MRD level in ECOG-ACRIN E1910 Hemasphere 2023 7 33 EHA 2023 Hybrid Congress S115. 10.1097/01.HS9.0000967372.19440.62
34 Luger SM Sun Z Mattison RJ Paietta E Roberts KG Zhang Y Racevckis J Lazarus HM Rowe JM Arber DA Assessment of outcomes of consolidation therapy by number of cycles of Blinatumomab received in newly diagnosed measurable residual disease negative patients with B-lineage acute lymphoblastic leukemia: in the ECOG-ACRIN E1910 randomized phase III national clinical trials network trial Blood 2023 142 suppl 1 2877 10.1182/blood-2023-189648
35 Gu ME Zhang JY Tang YM Xu WQ Song H Xu X The effectiveness of Blinatumomab in clearing next-generation sequencing measurable residual disease in pediatric patients with B-cell acute lymphoblastic leukemia Blood 2023 142 suppl 1 6076 10.1182/blood-2023-179796
36 Stein AS Kantarjian H Gokbuget N Bargou R Litzow MR Rambaldi A Ribera JM Zhang A Zimnmerman Z Zugmaier G Blinatumomab for acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation Biol Blood Marrow Transplant 2019 Aug 25 8 1498 1504 Epub 2019 Apr 17 10.1016/j.bbmt.2019.04.010 31002989
37 Gaballa MR Banerjee P Milton DR Jiang X Ganesh C Khazal S Nandivada V Islam S Kaplan M Daher M Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia Blood 2022 139 1908 1919 10.1182/blood.2021013290 34914826
38 Webster JA Jones RJ Blackford A Shedeck A Ambinder RF Swinnen LJ Wagner-Johnston N Fuchs EJ Bolanos-Meade J Imus P A phase IB/II study of Blinatumomab in patients with B-cell acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL) as post-allogeneic blood or marrow transplant (alloBMT) remission maintenance Blood 2023 142 suppl 1 3582 10.1182/blood-2023-191047
39 Chauvet P Paviglianiti A Labopin M Labussiere H Boissel N Robin M Maillard N Ouachée-Chardin M Forcade E Poiré X Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: a study of the SFGM-TC Bone Marrow Transplant 2023 58 72 79 10.1038/s41409-022-01846-9 36261707
40 Brown PA Ji L Xu X Devidas M Hogan LE Borowirtz MJ Raetz EA Zugmaier G Sharon E Bernhardt MB Effect of post-reinduction therapy consolidation with Blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial JAMA 325 833 842 10.1001/jama.2021.0669 33651090
41 LocatellI F Eckert C Hrusak O Buldini B Sartor M Zugmaier G Zeng Y Pilankar D Morris J von Stackelberg A Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-.risk first relapse B-cell precursor acute lymphoblastic leukemia Pediatr Blood Cancer 2022 69 e29715 10.1002/pbc.29715 35482538
42 Sayyed A Chen C Gerbitz A Pretransplant blinatumomab improves outcomes in B cell acute lymphoblastic leukemia patients who undergo allogeneic hematopoietic transplantation Transplant Cell Ther 2024 in press 10.1016/j.jtct.2024.03.004 38462215
43 Llaurador G Shaver K Wu M Wang T Gillispei A Doherty E Craddock J Read J Yassine K Morales E Blinatumomab therapy is associated with favorable outcomes after allogeneic hematopoietic cell transplantation in pediatric patients with B cell acute lymphoblastic leukemia Transplant Cell Ther 2024 30 217 227 10.1016/j.jtct.2023.10.024 37931800
44 Foa R Bassan R Vitale A Elia L Piciocchi A Puzzolo MC Canichella M Viero P Ferrara F Lunghi M Fabbiano F Dasatanib-Blinatumomab for pH-posotive acute lymphoblastic leukemia in adults N Engl J Med 2020 383 1613 1623 10.1056/NEJMoa2016272 33085860
45 Foa R Bassan R Elia L Piciocchi A Soddu S Messina M Ferrara F m Lunghi M Mulè A Bonifacio M Fracchiolla N Long-term results of the dasatanib-blinatumomab protocol for adult Philadelphia-positive ALL J Clin Oncol 2024 42 8871 885 10.1200/JCO.23.01075 38127722
46 Advani AS Moseley A O’Dwyer KM Wood BL Park J Wieduwilt M Jeyakumar D Yaghmour G Atallah EL Gerds AT Dasatanib/prednisone induction followed by blinatumomab/dasatanib in Ph+ acute lymphoblastic leukemia Blood Adv 2023 7 1279 1285 10.1182/bloodadvances.2022008216 36322825
47 Advani AS Moseley A O’Dwyer KM Wood BL Park J Wieduwilt M Jeyakumar D Yaghmour G Atallah EL Gerds AT Long-term follow up for SWOG 1318: combination of dasatanib, prednisone, and Blinatumomab for older patients with Philadelphia-chromosome (Ph) positive acute lymphoblastic leukemia (ALL) Blood 2023 142 suppl 1 1499 10.1182/blood-2023-180204
48 Geyer MB Mascarenhas J Smith M pacsual S shah A Sivestrone MR Czaplinska T Johnson K Thompson MC Park JH Chemotherapy-sparing induction followed by consolidation and maintenance with Blinatumomab and concurrent tyrosine kinase inhibitor therapy for newly-diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: primary endpoint results from the Bissphall study Blood 2023 142 suppl 1 1510 10.1182/blood-2023-173551
49 Jabbour E Short NJ Jain N Huang X Montalban-Bravo G Banerejee P Rezvani K Jiang X Kim KH Kanagal-Shamanna R Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukemia: a US, single-centre, single-arm, phase 2 trial Lancet Hematol 2023 10 e24 e34 10.1016/S2352-3026(22)00319-2 36402146
50 Haddad FJ Jabbour E Short NJ Jain N Huang X Montalban-Bravo G Kadia TM Daver N Nasnas C Major E Chemotherapy-free combination of Blinatumomab and ponatinib in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: updates from a phase II trial Blood 2023 142 suppl 1 2827 10.1182/blood-2023-188064
51 Chiaretti S Leoncin M Elia L Piciocchi A Matarazzo M Di Trani M Sica S Luppi M Mancini V Borlenghi E Comparison between dasatinib-blinatumomab vs ponatinib-blinatumomab chemo-free strategy for newly diagnosed Ph+ acute lymphoblastic leukemia patients. Preliminary results of the Gimema ALLL2820 trial Blood 2023 142 suppl 1 4249 10.1182/blood-2023-189632
52 Jabbour E Kantarjian HM Koller PB Jamy O Oehler VG Lomaia E Hunter AM Uspenskaya O Samarina S Mukherjee S Update of olvermbatinib (HQP1351) overcoming ponatinib and/or asciminib resistance in patients (Pts) with heavily pretreated/refractory chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Blood 2023 142 suppl 1 1798 10.1182/blood-2023-187744
53 Li Z Ting Z Hu L Duan W Jiang Q Olvermbatinib (HQP1351) combined with chemotherapy is an effective and safe treatment in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blast phase (CMN-LBP) that failed TKI-based regimens Blood 2023 142 suppl 1 5895 10.1182/blood-2023-185471
54 Fan S Wang L Lu Y Li Z Olvermbatinib combined with Blinatumomab in treating T315I-mutated Philadelphia chromosome-positive acute lymphoblastic leukemia: two-case report Ann Hematol 2024 103 525 532 10.1007/s00277-023-05519-5 37940719
55 Zhang T Zhu K Zihong C Lin R Liu Q Zhou H Frontline combination of 3rd generation TKI Olvermbatinib and Blinatumomab for Ph+/Ph-like ALL patients Blood 2023 142 suppl 1 1504 10.1182/blood-2023-186139 37917082
56 Kantarjian H Short NJ Jain N Sasaki K Huang X Haddad FG Khouri I DiNardo CD Pemmaraju N Wierda W Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-months follow-up results Am J Hematol 2023 98 493 501 10.1002/ajh.26816 36600670
57 Jen WY Jabbour E Haddad FGF Nasr L Short NJ Zoghbi M Nasnas C Issa GC Yilmaz M Daver N A phase II study of low-intensity chemotherapy (Mini-hyper-CVD) and ponatinib followed by Blinatumomab and ponatinib in patients with Philadelphia-positive acute lymphoblastic leukemia Blood 2023 142 suppl 1 2868 10.1182/blood-2023-182997
58 Schwartz M McMahon CM Amaya ML Witkowski M Pollkyea DA Gutman JA Minajuddin M Smith C Jordan CT Consolidation with ponatinib plus sequential Blinatumomab and chemotherapy after low intensity dasatinib-based induction in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: outcomes from a single institution Blood 2023 142 suppl 1 4247 10.1182/blood-2023-188118
59 Chiaretti S Della Starza I Santoro A Spinelli O Elia L De Propris MS Piccini M Chiusolo P Ferrara F Zappasodi P Sequential chemotherapy and Blinatumomab to improve minimal residual disease in dult Ph-B-lineage acute lymphoblastic leukemia. Final results of the phase II GIMEMA LAL2317 trial Blood 2023 142 suppl 1 826 10.1182/blood-2023-174973
60 Tasian SK Loh ML Hunger SP Philadelphia chromosome-like acute lymphoblastic leukemia Blood 2017 130 2064 2072 10.1182/blood-2017-06-743252 28972016
61 Boissel N Huguet F Graux C Hicheri Y Chevalier P Kim R Balsat M Leguayt T Hunault M Maury S Frontline consolidation with Blinatumomab for high-risk Philadelphia-negative acute lymphoblkastic adult patients. Early results from the Graall-2014-QUEST phase 2 Blood 2021 138 suppl 1 1232 10.1182/blood-2021-146163
62 Boissel N Huguet F Leguay T Hunault M Kim R Hicheri Y Chevallier P Balsat M Maury S Thiebaut-Bertrand A Blinatumomab during consolidation in high-risk Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) adult patients : a two-cohorts comparison within the Graall-2014/B study Blood 2022 140 suppl 1 507 509 10.1182/blood-2022-159397
63 Boissel N Huguet F Leguay T Hunault M Kim R Hicheri Y Passet M Chevallier P Balsat M Maury S Exploring the heterogeneity of response to Blinatumomab in high-risk Philadephia-negative B-cell precursor acute lymphoblastic leukemia: an analysis from the QUEST sub-study of the Graall 2014/B trial Blood 2023 142 suppl 1 499 10.1182/blood-2023-177847 37561543
64 Fleming S Reynolds J Bajel A Venn N Kwan J Moore J Yeung D Pati N Lehy M Nkyekyer J Lymphoma group ALLo8 study Blood 2021 138 suppl 1 1234 10.1182/blood-2021-151826
65 Fleming S Reynolds J Bajel A Venn N Kwan J Moore J Yeung D Pati N Lehy M Kollipara S Sequential Blinatumomab with reduced intensity chemotherapy for older adults with newly diagnosed Ph-Bprecursor acute acute lymphoblastic leukemia-Final results of the ALLG ALL08 study Hemasphere 2023 7 suppl 1 e811479d 10.1097/01.HS9.0000968372.81147.9d
66 Goekbuget N Schwartz S Faul C Topp MS Subklewe M Renzelmann A Stoltefuss A Artenstein B Wilke A Raffel S Dose reduced chemotherapy in sequence with Blinatumomab for newly diagnosed patients with Ph/BCR:ABL negative B-cell precursor adult lymphoblastic leukemia 8ALL): preliminary results of the GMALL bold trial Blood 2023 142 suppl 1 964 10.1182/blood-2023-180472
67 Nguyen D Kantarjian HM Short NJ Jain N Haddad FG Yilmaz M Ferrajoli A Kadia TM Valero YA Maiti A Updated results from a phase II study of hyper-CVAD, with or without inotuzumab ozogamicin, and sequential Blinatumomab in patients with newly diagnosed B-cell acute lymphoblastic leukemia Blood 2023 142 suppl 1 4245 10.1182/blood-2023-190902
68 Van der Sluis I De Lorenzo P Kotecha RS Attarbaschi A Escherich G Nysom Stary J Ferster A Brethon B Locatelli F Schrappe M Blinatumomab added to chemotherapy in infant lymphoblastic leukemia N Engl J Med 2023 8 1572 1581 10.1056/NEJMoa2214171 37099340
69 Schrappe M Locatelli F Valsecchi MG Cario G Vossen-Gajcy M Stary J Attarbaschi A Bodmer N Barbaric D Elitzur S Pediatric patients with high-risk B-cell LL in first complete remission may benefit from less toxic immunotherapy with Blinatumomab - Results from randomized controlled phase 3 trial AIEOP-BFM ALL 2017 Blood 2023 142 suppl 1 825 10.1182/blood-2023-181524
