919632 research-article20202020 TAH0010.1177/2040620720919632Therapeutic Advances in HematologyJ-M Ribera, E Genescà Therapeutic Advances in Hematology Review Bispecific T-cell engaging antibodies in Ther Adv Hematol 2020, Vol. 11: 1–15 B-cell precursor acute lymphoblastic DOI: 10.1177/ https://doi.org/10.1177/2040620720919632 https://doi.org/10.1177/2040620720919632 2040620720919632 leukemias: focus on blinatumomab © The Author(s), 2020. Article reuse guidelines: sagepub.com/journals- permissions Jose-Maria Ribera , Eulalia Genescà and Jordi Ribera Abstract: Bispecific T-cell engaging antibodies are constructs engineered to bind to two different antigens, one to a tumor-specific target and the other to CD3-positive T cells or natural killer (NK) cells. Blinatumomab engages CD19 and CD3, performing effective serial lysis. The clinical development program in acute lymphoblastic leukemia (ALL) includes clinical trials in relapsed or refractory (R/R) patients and in B-cell precursor (BCP) ALL patients with measurable residual disease. Several trials are currently being conducted in de novo BCP-ALL, either in induction, consolidation, or before or after hematopoietic stem cell transplant. Combination with other targeted therapies or with other immunotherapeutic approaches are also underway. Several strategies are aimed to optimize the use of blinatumomab either by overcoming the mechanisms of resistance (e.g. inhibition of PD-1/PD- L1) or by improvements in the route of application, among others. Keywords: acute lymphoblastic leukemia, B-cell precursor, bispecific antibodies, blinatumomab, review Received: 6 December 2019; revised manuscript accepted: 5 March 2020. Introduction 10%.7 Predictors for outcomes include: patient Correspondence to: Jose-Maria Ribera With the current treatment of acute lymphoblas- age, duration of first remission, response to ini- Clinical Hematology tic leukemia (ALL), cure is achieved in 90% of tial salvage therapy, and ability to undergo Department, ICO-Hospital Germans Trias I Pujol, children and 40–50% of adults. The main reasons alloHSCT. For patients who are candidates for Josep Carreras Research for failure are resistant disease (RD) and relapse. salvage therapy, the choice of regimens considers Institute, Universitat Autònoma de Barcelona, The frequencies of both events in children are less patient age and comorbidities, disease character- C/ Canyet, s/n, Badalona, than 5% and 10–15%, respectively, whereas in istics (e.g. immunophenotype, genetic character- 08916, Spain jribera@iconcologia.net adults 5–10% of patients are refractory to initial istics, extramedullary involvement, among Eulalia Genescà therapy, and an additional 30–60% of patients others), type of prior therapy, and duration of Jordi Ribera relapse despite aggressive consolidation and prior remission, among others.8 Although some Clinical Hematology Department, ICO-Hospital maintenance chemotherapy regimens, including new chemotherapeutic drugs have been approved Germans Trias i Pujol, allogeneic hematopoietic stem cell transplant for relapsed or refractory (R/R) patients (e.g. clo- Josep Carreras Research Institute, Universitat (alloHSCT). New complete response (CR) can farabine, nelarabine, vincristine liposome sul- Autònoma de Barcelona, be attained in 20–40% of patients, but these fate), the most promising results have been Badalona, Spain remissions are, in general, of short duration achieved with immunotherapy [monoclonal anti- despite the subsequent realization of alloHSCT. bodies (MoAb) and cellular therapy]. Prolonged disease-free survival (DFS) and cure are observed in around 10–15% of relapsed patients (Table 1).1–7 A study including 1706 Unconjugated and antibody-drug conjugated adult patients with R/R B-cell precursor (BCP) MoAb in ALL ALL from several European and North American There are three types of MoAb constructs used groups reported 3-year survival rates of only in ALL therapy: unconjugated, antibody-drug journals.sagepub.com/home/tah 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Hematology 11 Table 1. Results of representative studies of salvage chemotherapy in R/R ALL. Study Thomas et al.1 Fielding et al.2 Oriol et al.4 Gokbuget et al.5 Kozlowski et al.6 n 314 609 263 547 71 CR (%) 31 NA 45 42 52 Early death (%) 21 NA 17 NA 4 Refractory (%) 49 NA 38 NA 44 HSCT in ⩾CR2 (%) NA 25 30 75 62 CR duration 6 months NA 6 months NA NA (median) OS (median) 5 months 24 weeks 4.5 months 8.4 months 9 months OS probability 3% (5 years) 7% (5 years) 10% (5 years) 24% (3 years) 15% (5 years) Prognostic factors Age < 40 years Age < 20 years Age < 30 years Age < 25 years Age < 35 years CR1>1 year CR1 >2 years CR1 >2 years CR1>1.5 year CR1 >1.5 year No blasts in PB Response to Response to 1st 1st/2nd salvage salvage ALL, acute lymphoblastic leukemia; CR, complete response; CR1, first complete response; CR2, second complete response; HSCT, hematopoietic stem cell transplant; N, number of patients; NA, not available; OS, overall survival; R/R, relapsed/refractory. conjugated (ADC), also known as immunoconju- promising results in patients with R/R ALL and gated, and bispecific.9 The latter type are the sub- could represent a step ahead in treating these ject of this review. patients. Furthermore, results from a phase II trial with reduced doses of InO in combination Rituximab, combined with front-line standard with the so-called mini hyperCVD chemotherapy chemotherapy, has demonstrated to improve schedule in patients aged 60 years or older with event-free survival (EFS) in one prospective ran- newly diagnosed ALL showed a 85% CR rate and domized study from the GRAALL intergroup.10 an estimated progression-free survival of 59% at Rituximab has also proven to improve the results 2 years, with a median OS not reached.14 of treatment of newly diagnosed patients with Burkitt’s lymphoma or leukemia.11 Chimeric antigen receptor T-cells Epratuzumab, a naked humanized anti-CD22 Chimeric antigen receptor T (CAR-T) cells tar- MoAb has been explored in combination with geting the CD19 antigen have generated highly clofarabine and high dose cytarabine in adult promising results in children and adults with R/R patients with relapsed disease with a response rate ALL (Table 2).15–21 Overall response rates ranged of 52%.12 Inotuzumab ozogamicin (InO), a from 67% to 97% in patients who were actually humanized anti-CD22 MoAb conjugated to cali- infused, with complete measurable residual dis- cheamicin, has been approved to treat patients ease (MRD) response achieved in the vast major- with R/R CD22-positive BCP-ALL on the basis ity of responders. From the results of the global of the randomized INO-VATE study, which multi-institutional ELIANA trial,20 tisagenlecleu- showed significantly better response rate and cel was approved by both United States (US) and overall survival (OS) compared with standard-of- European Union (EU) agencies to treat patients care rescue therapy.13 Liver-related adverse events aged 1–25 years with BCP-ALL in second relapse were more common in the InO group, with an or in relapse after HSCT. Cytokine release syn- 11% incidence of hepatic sinusoidal obstruction drome (CRS) and neurotoxicity are common, syndrome (SOS) versus 1% in the standard-­ and sometimes severe, with CAR-T as compared therapy group. The concurrent combination of with bispecific MoAb such as blinatumomab, attenuated chemotherapy and InO showed likely because of massive induced CAR-T 2 journals.sagepub.com/home/tah J-M Ribera, E Genescà et al. Table 2. Main results of CD19 CAR T studies on ALL. Author, Institution Costimulatory Age Infused ORR % CRS, % Neurotoxicity, % OS reference domain (median, range) N Maude UPenn 4-1BB 14 years 30 90% 100% 43% 78% at et al.15 (5–60) (severe, 27%) 6 months Davila MSKCC CD28 50 years 16 88% severe, 44% Gr 3/4, 25% NA et al.16 (NA) Lee et al.17 NCI CD28 15 years 21 67% 76% 29% 52% at (5–27) (Gr 3/4, 29%) (Gr 3/4, 5%) 12 months Turtle FHCRC 4-1BB 40 years 30 93% 83% 50% NA et al.18 (20–73) (Gr 3/4, 50%) Gardner SCRI 4-1BB 12 years 43 93% 93% 49% 69.5% at et al.19 (1–25) (Gr 3/4, 23%) (Gr 3/4, 21%) 12 months Maude Novartis 4-1BB 11 years 751 81% 77% 40% 76% at et al.20 (3–23) (Gr 3/4, 13%) 12 months Park MSKCC CD28 44 years 532 83% 85% 48% median, et al.21 (23–74) (Gr 3/4, 26%) (Gr 3/4, 42%) 12.5 months 1Screened: 92; 2Screened: 75. ALL, acute lymphoblastic leukemia; CAR-T, chimeric antigen receptor T; CRS, cytokine release syndrome; FHCRC, Fred Hutchinson Cancer Research Center; Gr, grade; MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute; ORR, overall response rate; OS, overall survival; SCRI, Seattle Children’s Research Institute; UPenn, University of Pennsylvania. expansion/activation and endothelial activation.22 There are two main types of bispecific MoAb: Many issues still need to be elucidated, including CD3 bispecific formats and CD16 (NK) bispe- CAR-T composition, CAR-T persistence, the cific formats. Currently there are more than 100 role of prior allogeneic HSCT and disease burden different formats, including bispecific antibody at infusion time on CAR-T efficacy, and the T-cell engagers (BiTE), bispecific antibody-armed mechanisms of resistance, among others. activated T-cells (BAT), dual-affinity re-targeting Genetically engineered “off-the-shell” allogeneic bispecific antibodies (DART), tetravalent bispe- CAR-T, aiming to increase the applicability and cific tandem diabodies (TandAb), T-cell depend- rapidity of the procedure, are under clinical devel- ent bispecific antibody (TDB) and trifunctional opment. Due to a relatively high incidence of antibodies (Trifab or Triomab), among oth- CD19-negative ALL recurrence, strategies com- ers.24–26 This review focuses only on BiTE, and bining CD19 CAR T with immune checkpoint specifically blinatumomab, the only BiTE MoAb inhibitors, or simultaneous CD19 and CD22 tar- approved for treating BCP-ALL. geting using bispecific or bicistronic CAR-T, are also being investigated. Blinatumomab for the treatment of ALL BiTE MoAb are built by joining two single-chain Bispecific T-cell engaging MoAb Fv fragments: one targeting a neoplastic cell and Bispecific MoAb are engineered to bind to two the other targeting CD3.27 Blinatumomab is the different antigens or two different epitopes on the first bispecific MoAb, anti CD19-Anti CD3, that same antigen. They are used mostly to redirect allows CD3-positive T-lymphocytes to eliminate the cytotoxic potential of immune effector cells CD19-positive B-lymphocytes, including malig- [T-cells or natural killer (NK) cells] to the nant lymphoid B-cells from lymphomas and destruction of tumor cells.23 The redirection of BCP-ALL blasts, being either Philadelphia (Ph) T-cells to tumors is not restricted by major histo- chromosome-positive or not.28 As a result of a compatibility complex, thus obviating the need preferential affinity to CD19, CD3 T-cells can for antigen recognition by the T-cell receptor. move from one B-cell to another, resulting in journals.sagepub.com/home/tah 3 Therapeutic Advances in Hematology 11 Figure 1. Mechanism of action of blinatumomab. CD, cluster of differentiation; TNF, tumor necrosis factor. Table 3. Main results of clinical trials with blinatumomab in ALL. Type of ALL Ph-positive, Ph-negative, R/R adults Positive Ph-negative, Ph-negative, R/R adults MRD, adults R/R, children R/R, children Study Pivotal First Confirmatory phase III phase II phase I/II phase II phase II phase II phase II TOWER BLAST Study 205 expanded (ALCANTARA) access (RIALTO) Patients (N) 45 36 189 271 116 70 98 CR/CRh (%) 36 69 43 45 NA 39 60 MRD level <0.01% 88 88 82 76 78 54 48 OS, median, months 7.1 9.8 6.1 7.7 36.5 7.5 13 ALL, acute lymphoblastic leukemia; CR, complete remission; CRh, complete remission with incomplete hematologic recovery; MRD, measurable residual disease; OS, overall survival; R/R, relapsed or refractory. serial lysis through a perforin/granzyme-mediated Administration (FDA) and European Medical mechanism (Figure 1).29 Agency (EMA) for treatment of adult and pediatric patients with R/R and MRD-positive BCP ALL. The clinical development program of blinatu- momab included phase II studies in patients with R/R ALL, with and without Ph chromosome in Phase II and related studies with adults and in children, a phase III trial comparing blinatumomab as a single drug in R/R and blinatumomab as single drug versus standard-of- MRD-positive ALL care (SOC) rescue chemotherapy in adults with R/R Ph-negative ALL, and a phase II study in adult Studies in relapsed or refractory patients with Ph-negative ALL in MRD-positive Ph-negative ALL status (Table 3).30,31 As a result of these studies, The first exploratory phase II study (ClinicalTrials. blinatumomab is the first T-cell engager molecule gov identifier: NCT01209286) on blinatumomab approved by both the US Food and Drug in patients with R/R BCP-ALL was performed in 4 journals.sagepub.com/home/tah J-M Ribera, E Genescà et al. 36 patients by the German Multicenter Adult despite a higher frequency of alloHSCT in Acute Lymphoblastic Leukemia (GMALL) younger adults (59% versus 15%). The tolerabil- group.32 This study included a search for opti- ity was similar for both groups of patients, mal dose schedule, and found an initial dose of although older adults showed more grade ⩾3 5 μg/m2/day for 7 days followed by 15 μg/m2/day neurologic events (28% versus 13%). for the subsequent 3 weeks as the schedule asso- ciated with the lowest rate of adverse events A subset analysis was performed for patients with (AE). In addition, debulking with dexametha- BCP-ALL from the global phase II trial who had sone and cyclophosphamide was recommended relapsed following alloHSCT (n = 64).36 The CR/ in patients with a high number of blasts before CRh rate was 45% (29 of 64), with molecular initiating blinatumomab therapy. The rate of response in 22 of 29 (complete MRD response in CR and CR with incomplete hematologic recov- 19 out of 22). The median RFS was 7.4 months ery (CRi) was 69%, with median OS of for patients who achieved CR/CRh in the first two 9 months,32 with longer survival for patients cycles, and the median OS was 8.5 months. The achieving MRD-negative status.33 tolerability of blinatumomab did not differ from that of the remaining patients. Interestingly, seven A subsequent pivotal global multicenter phase II patients experienced grade 3 or less graft-versus- study (ClinicalTrials.gov identifier: NCT0146 host disease (GVHD) during the study, none of 6179),34 included 189 adult patients with R/R, which resulted in discontinuation of blinatu- Ph-negative ALL. Patients with poorer character- momab or hospitalization. istics than that of the previous trial were included: higher disease burden [>10% bone marrow (BM) As achievement of MRD response is a major goal blast cells, refractoriness (failure to frontline ther- for ALL patients in CR, an analysis of molecular apy), CR duration <12 months], or cases beyond response in CR/CRh patients treated within the first relapse. The blinatumomab schedule con- global phase II study was performed.37 MRD sisted of 9 μg/day for the first 8 days and 28 μg/day response after 2 blinatumomab cycles was thereafter for 3 weeks for the first cycle, followed achieved in 83% (75/90) of patients in CR/CRh. by 28 μg/day for subsequent cycles, with a 14-day This was translated into improved OS and RFS in interval between cycles. One or two cycles were patients who achieved MRD response (medians, scheduled as induction followed by 1–3 cycles as 20.6 versus 9.0 months, respectively for OS and consolidation. The rate of CR or CR with incom- 12.5 versus 2.3 months, respectively for RFS). plete hematologic recovery (CRh) was 43%, Thus, achieving MRD response can be used as a being achieved by cycle 1 in 79% of responders. prognostic factor for blinatumomab treatment in After the first two cycles, 82% of responders R/R ALL. achieved an MRD level <10–4. MRD responders showed a significantly improved OS (11.5 months A long-term follow-up analysis combining versus 6.7 months for non-responders). A subse- patients from the exploratory GMALL study and quent alloHSCT was performed in 40% of CR/ those of the global phase II study is being con- CRh patients. Based on the results of this trial, ducted to evaluate the OS and the characteristics blinatumomab received accelerated US FDA of patients with long-term survival. In addition, a approval for the treatment of Ph–negative R/R retrospective observational study (NEUF) includ- B-ALL in December 2014. ing 253 patients treated with blinatumomab in the expanded access program between January A comparison of the results of blinatumomab 2014 and December 2016 in five European coun- therapy in elderly patients from the two afore- tries was recently concluded and presented in mentioned studies (⩾65 years, n = 36) with abstract form.38,39 Within two cycles of blinatu- results in younger adults (<65 years, n = 225)35 momab, 54 (51%) patients achieved CR/CRh, of showed a similar CR/CRh and MRD response whom 91% (49/54) had CR, and 85% of CR rate after two cycles (56% versus 46%, respec- patients achieved molecular response. One-third tively, for CR/CRh and 60% versus 70%, respec- of patients proceeded to alloHSCT. Outcomes tively, for MRD response). Similarly, relapse-free were better in patients with hematologic response survival (RFS) and OS were not significantly dif- compared with those without and in patients with ferent (median RFS 7.4 months for both groups; MRD response compared with those without. median OS 5.5 versus 7.6 months, respectively), Overall, these results are widely consistent with journals.sagepub.com/home/tah 5 Therapeutic Advances in Hematology 11 published results from the global phase II clinical blinatumomab in patients with R/R Ph-positive trial and confirm the effectiveness of blinatu- ALL. Adult patients with Ph-positive ALL who momab in a real-world setting. had relapsed after or were refractory to at least one second-generation or later tyrosine kinase A phase I/II clinical trial in R/R pediatric ALL inhibitors (TKI) or were intolerant to second- (ClinicalTrials.gov identifier: NCT01471782) generation or later TKI and intolerant or refrac- established the dose of blinatumomab of 5 μg/m2/ tory to imatinib were included.43 Out of 45 day for 7 days followed by 15 μg/m2/day for the patients, 16 (36%) achieved CR/CRh during the remaining 3 weeks of the first and subsequent first two cycles. Notably, CR/CRh was attained in cycles.40 The 70 patients included in the phase II 4/10 patients with the T315I mutation; 88% of trial received the complete dosage. After the first CR/CRh patients achieved complete molecular two cycles, 27 patients (39%) achieved CR, with response, and 44% of patients in CR/CRh under- 14 (52%) becoming MRD negative. The frequency went alloHSCT. The median RFS and OS were of side effects was similar to that observed in previ- 6.7 and 7.1 months, respectively. From these ous trials in adults. This trial provided evidence of results it seems clear that the efficacy (and safety) the efficacy and tolerability of blinatumomab also of blinatumomab are similar in R/R patients in children with R/R ALL. The final results of this with Ph-negative or -positive ALL. This prompted trial were published in 2018.41 The median OS was FDA approval of blinatumomab for R/R 7.5 months, with a 2-year OS probability of 25%, Ph-positive ALL in July 2017. and 31% of patients (22 of 70) were alive. Failure to respond (n = 30) and relapse (n = 15) were the An observational retrospective study performed major causes of death. OS was longer in patients in patients with R/R Ph-positive ALL compared with complete MRD response (14.6 months versus outcomes of patients treated with blinatumomab 5.7 months for non-MRD responders). in the phase II trial with those of historical control patients with similar characteristics treated with An open label, multicenter, expanded access the SOC in Italy and Spain.44 Propensity score study (RIALTO trial, ClinicalTrials.gov identi- analysis (PSA) was used to compare outcomes. fier: NCT02187354) was initiated in 2014 for The rate of CR/CRh was 36% for blinatumomab pediatric patients with R/R BCP-ALL.42 and 25% for SOC. OS favored blinatumomab Blinatumomab was scheduled for up to 5 cycles, over SOC, with a hazard ratio of 0.77 [95% con- although patients could proceed to alloHSCT fidence interval (CI), 0.61–0.96]. once CR had been achieved. At the last data cut- off, 37 out of 98 patients were under study. The most frequent grade ⩾3 AE (the main objective Studies in MRD-positive ALL of the study) were cytopenias (31%), infections A step ahead in the development program of bli- (16%), raised liver enzymes (12%), neurologic natumomab included the evaluation of activity events (5%), CRS (2%), and tumor lysis syn- in patients with MRD-positive ALL in either drome (2%). None of the nine fatal AE was first morphologic CR or in relapsed ALL. It is of related to blinatumomab. The CR/CRh rate was note, however, that the first clinical trial with 60%, and 27 out of 59 patients who achieved CR blinatumomab (ClinicalTrials.gov identifier: within two cycles received alloHSCT. The NCT00560794) in ALL was conducted by the median OS was 13 months (median follow up GMALL group in a small group of adults with 12.2 months for all 98 patients), disease progres- BCP ALL with molecular failure (n = 15) or sion being the main cause of death (32 of 38 relapse (n = 5) after consolidation of front-line patients). Data from the RIALTO study confirm therapy.45 The rate of molecular CR (80%, 16/20 the effectiveness and tolerability of blinatumomab evaluable patients) was similar to that attained in in children with R/R BCP ALL. cases of R/R ALL. Interestingly, an extended fol- low up of this study showed no differences in sur- vival for patients who received alloHSCT (n = 9) Studies in R/R Philadelphia chromosome- or not (n = 11).46 positive ALL A multicenter phase II trial (ALCANTARA, The most interesting results from blinatumomab ClinicalTrials.gov identifier: NCT02000427) was in MRD-positive status came from the BLAST conducted to assess the efficacy and tolerability of trial (ClinicalTrials.gov identifier: NCT01207388), 6 journals.sagepub.com/home/tah J-M Ribera, E Genescà et al. a multicenter, phase II study conducted to evalu- Phase III and related studies with ate the efficacy, safety, and tolerability of blina- blinatumomab as a single drug in R/R ALL tumomab in adult patients with MRD-positive A phase III randomized trial (TOWER, BCP-ALL.47 This trial included patients in CR ClinicalTrials.gov identifier: NCT02013167) after ⩾3 intensive chemotherapy treatments and compared blinatumomab with conventional SOC with MRD ⩾10–3. The primary endpoint was salvage chemotherapy, with either of the follow- complete MRD response (MRD negativity) after ing schedules: FLAG (fludarabine + high-dose one cycle. The trial accrued 116 patients, 65% cytarabine arabinoside ± anthracycline), high- of whom were in first CR. Complete MRD dose ARA-C, high-dose ARA-C ± anthracycline, response was attained in 91/113 evaluable high-dose methotrexate-based regimen or clofar- patients (78%), being achieved after the first abine based regimens) at a 2:1 ratio in adult cycle in 82. The complete MRD rates did not patients with R/R, Ph-negative ALL.48 The inclu- differ according to the level of MRD positivity sion criteria, as well as the blinatumomab dosing, and CR status. The medians of RFS and OS for were similar to those from the aforementioned the whole series were 18.9 and 36.5 months, phase II global trial, and the primary endpoint respectively (median follow up of 30 months). was OS. A total of 271 patients received blinatu- This compares favorably with the approximately momab and 134 received SOC therapy. 6–7 months observed in trials with R/R ALL.1–7 Significant differences in favor of blinatumomab Not surprisingly, outcomes were better in were observed for CR/CRh rate (44% versus patients treated in first CR (median EFS of 25%), MRD response (76% versus 48%), and OS 24.6 months versus 11 months for patients in sec- (median 7.7 versus 4.0 months), the latter being ond or later CR). A significantly longer OS was more evident in patients receiving blinatumomab achieved for patients who attained MRD as first salvage therapy (median OS of 11.1 versus response after one cycle (median 35.2 months 5.5 months).49 When the data were censored at versus 7.1 months for those without molecular the time of alloHSCT (performed in 24% of response). The rate of alloHSCT performed was patients from both groups), the medians of OS 67% (74 patients, 55 in first CR and 19 in sec- were 6.9 versus 3.9 months. On the basis of the ond CR), whereas 36 patients continued with results of the TOWER study, blinatumomab was the full blinatumomab schedule. Although eval- approved to treat patients with R/R, Ph-negative uation of the impact of alloHSCT after blinatu- BCP-ALL. momab treatment was not an objective of the BLAST trial, it is of note that no differences A recently published study analyzed the outcomes were observed in RFS according to transplanta- of patients in the TOWER trial who underwent tion in MRD-responsive patients treated in first alloHSCT after treatment with blinatumomab CR, whereas the RFS probability was better for (n = 65) or SOC (n = 32). No differences in sur- MRD-negative patients with second or later CR vival benefit were found.50 In addition, no sur- who underwent alloHSCT. The tolerability of vival benefit of alloHSCT versus no alloHSCT blinatumomab was similar to that of previous was observed in patients who achieved CR/CRh studies. A recent update of these data with a with blinatumomab. As expected, the best out- median follow-up of 59.8 months, confirmed the comes were observed in patients with MRD median OS of 36.5 months. Interestingly, the remission who received blinatumomab as first sal- median OS was not reached in patients with vage treatment regardless of subsequent perfor- complete MRD response versus 12.5 months in mance of alloHSCT. MRD non-responders. The proportion of sur- vivors was 40% in transplanted and 33% in The impact of blinatumomab on health-related non-transplanted patients. Based on the afore- quality of life (HRQL) as measured by the mentioned data, the regulatory authorities in the European Organization for Research and US and Europe extended the marketing authori- Treatment of Cancer (EORTC) Quality of Life zation for blinatumomab to MRD-positive BCP, Questionnaire QLQ-C30 was assessed in the Ph-negative ALL. A study aimed to compare phase III TOWER study.51 Patients treated with blinatumomab with historic SOC treatments for blinatumomab (n = 247) showed better HRQL MRD positive disease in adults with Ph-negative, across all QLQ-C30 subscales than those receiv- BCP-ALL is underway. ing chemotherapy (n = 95). journals.sagepub.com/home/tah 7 Therapeutic Advances in Hematology 11 The Childrens Oncology Group conducted a ran- phase. Although the number of evaluable patients domized phase III trial comparing blinatumomab was low (n = 14) and the follow up short, this regi- versus chemotherapy as post-reinduction therapy men has proven to be tolerable and effective.53 In in children and adolescent and young adults patients older than 65 years, preliminary results of (AYA) up to 30 years with high- and intermedi- the sequential application of blinatumomab and ate-risk BCP, Philadelphia chromosome-negative dose-reduced chemotherapy have been published ALL in first relapse. The first results of this trial in abstract form.54 The blinatumomab schedule have recently been published in abstract form.52 consisted of one to two cycles of induction until After receiving one block of reinduction chemo- the achievement of CR, followed by three addi- therapy, patients were randomized to receive tional consolidation cycles and 18 months of either two additional intensive reinduction cycles intensified maintenance therapy. The rate of CR/ of chemotherapy or four cycles of blinatumomab. CRi in 29 eligible patients (median age 75 years) After randomization, both groups proceeded to was 66%, and the treatment was tolerable with- alloHSCT. With a median follow up of 1.4 years, out deaths in induction. In a small retrospective the 2-year DFS (the main objective of the trial) study, blinatumomab was administered to chil- was 41% for the chemotherapy arm (n = 103 dren with BCP ALL with MRD-positive status patients) versus 59.3% for the blinatumomab arm before alloHSCT. A MRD-negative status was (n = 105 patients) (p = 0.05), and the 2-year OS achieved after one cycle in most of the chil- was 59.2% versus 79.4% (p = 0.005). The MRD dren. Blinatumomab was well tolerated and no response (<0.01%) was also better in the blinatu- transplant-related mortality was observed in momab arm (79% versus 21%, p < 0.0001), and the first 100 days after alloHSCT.55 The prelimi- the rate of alloHSCT was higher in patients nary results of a multicenter phase II trial with receiving blinatumomab (73% versus 45%, chemotherapy-free induction-consolidation trial ­ p < 0.0001). Fewer and less severe toxicities were (D-ALBA, GIMEMA LAL2116, ClinicalTrials. also observed in patients from the blinatumomab gov identifier: NCT02744768) based on the arm. Taken together, these data showed that bli- combination of dasatinib with blinatumomab in natumomab was superior to standard chemother- newly diagnosed Ph-positive ALL patients aged apy as post-reinduction consolidation prior to 18 years or older have recently been reported in alloHSCT in this specific group of patients. abstract form.55 Dasatinib (140 mg/day) was administered as induction for 85 days, combined with steroids during the first month. The consoli- Clinical trials with blinatumomab in newly dation treatment consisted of dasatinib combined diagnosed ALL with blinatumomab (minimum two cycles, but Table 4 shows the main clinical trials with blina- possible administration of three additional cycles tumomab in patients with newly diagnosed ALL. according to response and medical decision). The Most evaluated the use of blinatumomab during subsequent therapy was given at medical discre- consolidation in newly diagnosed patients with tion. At the primary time point (end of the second MRD positive after induction, while others incor- cycle of blinatumomab), 27/47 patients (56%) porated blinatumomab into first-line therapy presented molecular response (the main objective regardless of MRD status. Other approaches of the trial). Interestingly, the rate of molecular include the use of blinatumomab as prephase responses increased after subsequent cycles of bli- therapy of ALL, the preemptive use of blinatu- natumomab (66% and 80% after the third and momab after alloHSCT, or the combination of fourth cycle, respectively). With a median follow blinatumomab with other targeted therapies. In up of 10 months, 12 patients received alloHSCT Ph-positive ALL, studies with sequential applica- and six patients experienced relapse, with pro- tion of TKI and blinatumomab are underway. jected 12-months OS and DFS of 94% and 88%, respectively. Six out seven ABL mutations There is scarce published information on the detected before blinatumomab were not detected results of these studies. In one trial, young after blinatumomab therapy. Thus, this ongoing adults with BCP, Ph-negative ALL received the chemotherapy-free protocol for adult Ph+ ALL hyper-CVAD regimen (four cycles) as induc- patients combining targeted therapy and immu- tion, followed by four consecutive cycles of bli- notherapy shows good feasibility and promising natumomab as consolidation and a maintenance rates of molecular responses and survival. 8 journals.sagepub.com/home/tah J-M Ribera, E Genescà et al. Table 4. Selected clinical trials, active or in development, with blinatumomab (Blin) in de novo or R/R pediatric and adult ALL.1 ClinicalTrials.gov Schedule Planned n pts Age Status identifier De novo ALL, Ph-positive NCT03263572 Blin and ponatinib 60 ⩾60 Active NCT02744768 Dasatinib, prednisone and Blin 80 ⩾18 Active NCT02143414 Blin and CHT or Blin and dasatinib 44 ⩾65 Active De novo ALL. Ph-negative NCT02877303 Blin and HyperCVAD 60 ⩾14 Active NCT02458014 Blin in MRD-positive ALL 40 ⩾18 Active NCT03109093 Blin in MRD-positive ALL 60 ⩾18 Active NCT03541083 Blin prephase and CHT 80 18–70 Active NCT03480438 Blin and CHT 50 56–74 In preparation NCT03523429 CHT and Blin in consolidation in HR ALL 38 18–55 Active NCT03709719 Blin in HR ALL 95 18–59 Active NCT03643276 CHT and Blin in consolidation (randomized) 5000 <18 Active NCT02003222 CHT versus Blin in consolidation 509 30–70 Active NCT03367299 Sequential CHT and Blin 149 18–65 Active NCT03117751 CHT and Blin or others 1000 <18 Active NCT03114865 Blin maintenance after alloHSCT 12 ⩾18 Active NCT03751709 Blin and haploidentical HSCT 10 ⩾18 Active NCT02807883 Blin maintenance after alloHSCT 30 18–70 Active NCT02877303 Blin and inotuzumab 64 ⩾18 Active, also for R/R ALL NCT01371630 CHT, inotuzumab followed by Blin 256 56–74 Active Relapsed/refractory ALL NCT03518112 CHT and Blin 44 ⩾18 Active NCT02101853 CHT versus Blin (randomized) 598 1–30 Active NCT02393859 CHT versus Bin (randomized) 202 <18 Active NCT02997761 Blin and ibrutinib 20 ⩾18 Active NCT03628053 Blin or inotuzumab versus tisagenlecleucel 220 ⩾18 In preparation NCT03160079 Blin and pembrolizumab 24 ⩾18 Active NCT02879695 Blin and nivolumab w/o ipilimumab 30 ⩾16 Active 1ClinicalTrials.gov, accessed 15 October 2019. ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; Blin, blinatumomab; CHT, chemotherapy; HR ALL, high-risk ALL; NCT, National Clinical Trial; pts, patients; R/R, relapsed/refractory; w/o, with/without. journals.sagepub.com/home/tah 9 Therapeutic Advances in Hematology 11 Toxicity of blinatumomab were also found to be associated with resistance The most frequent grade ⩾3 AE observed with to blinatumomab.58 The outcome with blinatu- blinatumomab include febrile neutropenia, infec- momab in the R/R setting is also better in less tion, and hematological toxicities.34,40,42,47,48 Liver advanced stages of disease,49 with the presence of enzymes may show a transient increase as well additional mutations conferring resistance mech- but usually do not require infusion interruptions. anisms as the disease advances being the most Lymphopenia, as well as a decrease of immuno- probable reason. A history of prior extramedul- globulin levels, may be observed with prolonged lary ALL and current extramedullary ALL are infusion, but generally do not require immuno- also predictors of lower response rates, with 40% globulin supplementation. The two most impor- of relapses being located in the extramedullary tant specific AE are CRS and neurotoxicity. compartment.59 This could be explained by the lower accessibility of the immune system to some CRS is also observed with other immunothera- sanctuary extramedullary sites such as the central pies involving T lymphocytes such as CAR nervous system and others. T-cells, although the frequency and intensity are considerably lower with blinatumomab. With In the MRD setting, no pretreatment factor was pre-phase treatment in patients with high leuke- associated with inferior response, although long- mia burden, dose step, and pretreatment with term outcome was poorer in patients in a more dexamethasone, the incidence of CRS is less than advanced disease stage (i.e. later CR compared 5%.34,48 Blinatumomab must be discontinued if with first CR), as mentioned before.47 clinical manifestations of grade ⩾3 CRS appear. Anti-IL-6 treatment with tocilizumab or siltuxi- Some immunologic factors could provide insights mab is rarely needed. into the mechanisms of resistance to blinatu- momab. A study aimed at identifying biomarkers Neurologic AE are also common with CAR T for clinical outcomes of patients from the TOWER and blinatumomab.56 Their clinical spectrum is trial showed that a lower percentage of CD45+ highly variable, ranging from mild disorders such CD3– CD19+ B-cells was predictive of survival as tremor, headache, and dizziness, to severe in the blinatumomab group, whereas a higher symptoms of encephalopathy and seizures. This percentage of CD45+ CD3+ CD8+ T-cells was variability makes early detection extremely impor- predictive of hematologic remission in the blina- tant, as dexamethasone can be useful to reverse tumomab group. A higher percentage of CD3+ these early symptoms. However, if neurologic AE T-cells was prognostic of MRD response in both develop during blinatumomab infusion, treat- groups. No biomarker prognostic or predictive ment must be interrupted (most are quickly for grade ⩾3 neurologic events, infections, or reversible after interruption) and re-initiated at a cytokine release syndrome was identified.60 lower dose when they have disappeared.31,56 If Another study showed that a higher rate of T-cell they reappear after dose reduction, permanent expansion as well as a higher percentage of CD3- discontinuation of blinatumomab is mandatory. positive T-cells and lower levels of regulatory The pathogenic mechanisms of neurologic AE T-cells (Treg) were observed in long-term survi- are incompletely known, but the main suspected vors after blinatumomab treatment.58 The reduc- mechanism is an alteration of the blood–brain tion in the number of Treg with the systematic barrier as a consequence of endothelial activation use of cyclophosphamide in the preparative regi- of blood vessels caused by the adhesion of acti- men before blinatumomab administration could vated T-cells to the endothelium, followed by bypass this resistance mechanism.61 A reduced extravasation of these T-cells with cytokine level of cytotoxic CD8+ T-cells was also corre- release by extravasated T-cells in the brain.57 lated with non-response to blinatumomab.62 PD-L1 expression by lymphoblasts may inhibit T-cell function through the PD-1 receptor and Mechanisms of resistance to blinatumomab contribute to resistance to blinatumomab.62 In R/R BCP ALL, several trials showed a lower Inhibition of PD-1/PD-L1 with the concurrent rate of CR/CRh in patients with a higher degree administration of immune checkpoint inhibitors of BM blast infiltration, that is, >50%. High might increase the efficacy and reduce the resist- serum lactate dehydrogenase levels at relapse ance to blinatumomab,63 as observed in in vitro 10 journals.sagepub.com/home/tah J-M Ribera, E Genescà et al. studies, as well as was shown in a patient refrac- or sequential chemotherapy (full dose or dose- tory to blinatumomab in whom the combination reduced), combined use with targeted therapies of blinatumomab and pembrolizumab markedly (TKI and others) or with other immunothera- reduced leukemic burden.62 These observations peutic approaches (InO or CAR T-cells),68 the have led to the development of clinical trials com- systematic need for alloHSCT for patients suc- bining blinatumomab with nivolumab, ipili- cessfully treated at the MRD level or its preemp- mumab, orpembrolizumab in R/R ALL patients tive or prophylactic use after transplantation, (Table 4). among others. CD19-negative relapses are observed in around The optimization of blinatumomab (and of bispe- 10% of patients treated with blinatumomab.64 cific MoAb in general) can take place in several The selective pressure to CD19 may induce directions, such as the identification of reliable clonal selection of CD19-negative cells by CD19 predictive biomarkers and the use of strategies to loss due to different mechanisms. Among these overcome mechanisms of resistance, as discussed mechanisms, loss of the extracellular domain of previously. Improvement in the current route of CD19,65 conformational changes of the extracel- application (4-week intravenous continuous infu- lular domain of CD19 due to mutations, and sion) with the development of compounds with a intracellular accumulation of CD19 are the most prolonged half-life with other routes of adminis- important.66 Different strategies being used to tration (such as subcutaneous, ClinicalTrials.gov avoid this important problem include sequential identifier: NCT02961881) would improve the combination with other MoAb such as the ADC flexibility of treatment. Finally, continuous devel- anti-CD22 InO (Table 4), combination with TKI opment and improvement in the design of bispe- in Ph-positive ALL, or the sequential treatment cific or trispecific MoAb will constitute a step with CAR T-cells directed against other antigens forwards in the treatment of ALL and other (e.g. CD22), among others. hematologic neoplasms and solid tumors.69 In cases of BCP ALL with a very immature phe- Funding notype, such as KTMA-rearranged, relapses can The author(s) received no financial support for be associated with a lineage shift to acute myeloid the research, authorship, and/or publication of leukemia,67 this fact likely being due to the expan- this article. sion of CD19-negative clones after clearance of the CD19-positive dominant clone. Conflict of interest statement JM Ribera declares the following conflicts of interest: Pfizer: speaker and advisory boards hon- Conclusion oraria, clinical trials; AMGEN: speaker and advi- Bispecific T-cell engaging MoAb constitute a sory boards honoraria, research support, clinical very promising type of immunotherapy for hema- trials; Shire: speaker and advisory boards hono- tologic malignancies and solid tumors. Among raria; Ariad: speaker and advisory boards hono- them, blinatumomab is the most developed, and raria, clinical trials. The remaining authors is currently approved for clinical use in R/R and declare no conflicts of interest. MRD-positive BCP ALL in children and adults. Although results in the R/R setting are superior to ORCID iD those of SOC chemotherapy, they are not satis- Jose-Maria Ribera https://orcid.org/0000- factory. Attempts to overcome resistance mecha- 0003-1042-6024 nisms are underway. 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