Blood Cancer Journal www.nature.com/bcj ARTICLE OPEN Real-world use of blinatumomab in adult patients with B-cell acute lymphoblastic leukemia in clinical practice: results from the NEUF study ✉ Nicolas Boissel 1 , Sabina Chiaretti2, Cristina Papayannidis3, Josep-Maria Ribera 4, Renato Bassan 5, Andrey N. Sokolov 6 , Naufil Alam , Alessandra Brescianini8, Isabella Pezzani8, Georg Kreuzbauer8, Gerhard Zugmaier 9, Robin Foà2 and 7 Alessandro Rambaldi10 © The Author(s) 2022 This retrospective observational study (NEUF) included adult patients with B-cell acute lymphoblastic leukemia (B-cell ALL) who had received blinatumomab for the treatment of minimal residual disease-positive (MRD+) or relapsed/refractory (R/R) B-cell ALL via an expanded access program (EAP). Patients were eligible if blinatumomab was initiated via the EAP between January 2014 and June 2017. Patients were followed from blinatumomab initiation until death, entry into a clinical trial, the end of follow-up, or the end of the study period (December 31, 2017), whichever occurred first. Of the 249 adult patients included, 109 were MRD+ (83 1234567890();,: Philadelphia chromosome-negative [Ph−] and 26 Philadelphia chromosome-positive [Ph+]) and 140 had a diagnosis of R/R B-cell ALL (106 Ph− and 34 Ph+). In the MRD+ group, within the first cycle of blinatumomab treatment, 93% (n = 49/53) of Ph− and 64% (n = 7/11) of Ph+ patients with evaluable MRD achieved an MRD response (MRD <0.01%). Median overall survival (OS) was not reached over a median follow-up time of 18.5 months (Ph−, 18.8 [range: 5.1–34.8] months; Ph+, 16.5 [range: 1.8–31.6] months). In the R/R group, within two cycles of blinatumomab, 51% of Ph− and 41% of Ph+ patients achieved complete hematologic remission (CR/CRh/CRi), and 83% of Ph− and 67% of Ph+ MRD-evaluable patients in CR/CRh/CRi achieved an MRD response. Median (95% confidence interval) OS was 12.2 (7.3–24.2) months in the R/R Ph− subgroup and 16.3 (5.3–not estimated) months in the R/R Ph+ subgroup. This large, real-world data set of adults with B-cell ALL treated with blinatumomab confirms efficacy outcomes from published studies. Blood Cancer Journal (2023)13:2 ; https://doi.org/10.1038/s41408-022-00766-7 INTRODUCTION resulting in tumor cell lysis [4, 5]. The efficacy of blinatumomab Approximately 30–50% of patients with B-cell acute lympho- in patients with B-cell ALL has been demonstrated in various blastic leukemia (B-cell ALL) in complete hematologic remis- studies. In a Phase 2 trial in patients with MRD+ B-cell ALL, 78% sion (CR/CRh/CRi) exhibit post-induction minimal residual of patients receiving blinatumomab achieved a complete MRD disease (MRD) persistence, which indicates resistance to response, which was associated with longer relapse-free survival standard chemotherapy [1]. The presence of MRD-positive (RFS) and OS compared with MRD nonresponders [2, 6]. In two (MRD+) disease is also associated with a high relapse rate and single-arm Phase 2 studies, blinatumomab induced hematologic poor overall survival (OS) [1, 2], representing the most remission in heavily pretreated patients with R/R Philadelphia important risk factor for hematologic relapse in adult patients chromosome-negative (Ph−) B-cell ALL [7, 8]. In a Phase 3 trial, with B-cell ALL [3]. Patients with relapsed or refractory (R/R) treatment with blinatumomab resulted in longer median OS acute lymphoblastic leukemia (ALL) have poor long-term than standard chemotherapy [9]. MRD results were also survival and limited treatment options. MRD eradication is, analyzed in this patient population and showed longer OS for therefore, the goal for patients with B-cell ALL; this highlights MRD responders than for MRD nonresponders; the difference the importance of incorporating MRD assessment into routine was greater in first salvage than in second or later salvage clinical practice [3]. [10, 11]. In a Phase 2 trial in patients with R/R Ph+ B-cell ALL, Blinatumomab is a bispecific T-cell engager (BiTE®) molecule 36% of patients achieved complete remission (CR), of whom that directs CD3-expressing T cells to CD19-expressing B cells, 88% attained MRD negativity [12]. 1 Division of Hematology, EA3518 Saint-Louis Institute for Research, Saint-Louis Hospital, Paris, France. 2Hematology Department of Translational and Precision Medicine, “Sapienza” University, Rome, Italy. 3IRCCS, Azienda Ospedaliero Universitaria di Bologna, Institute of Hematology “Seràgnoli”, Bologna, Italy. 4Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain. 5Complex Operative Unit of Hematology, dell’Angelo Hospital and Santissimi Giovanni and Paolo Hospital, Mestre and Venice, Venezia-Mestre, Italy. 6National Research Center for Hematology, Moscow, Russian Federation. 7Amgen Ltd, Uxbridge, United Kingdom. 8Amgen (Europe) GmbH, Rotkreuz, Switzerland. 9Amgen Research (Munich) GmbH, Munich, Germany. 10Department of Oncology and Haematology, University of Milan and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. ✉email: nicolas.boissel@aphp.fr Received: 5 August 2022 Revised: 1 December 2022 Accepted: 2 December 2022 N. Boissel et al. 2 Evidence of real-world use of blinatumomab to date is based on Statistical analyses data from a compassionate use program in France, an ad hoc Analyses were descriptive and no formal hypothesis was tested [16]. Time- survey in Italy, and a retrospective cohort study in the USA to-event analysis (e.g., for OS, DFS, and RFS) was undertaken using [13–15]. These data sets demonstrated responses comparable to Kaplan–Meier (KM) methodology and using inverse KM estimates to those reported in clinical trials [2, 9]. calculate follow-up time. Mortality following allogeneic hematopoietic stem cell transplantation (HSCT) was evaluated as mortality not due to disease Before country-specific approval, blinatumomab was made relapse, treating relapse and death due to undocumented relapse as available to patients who met prespecified criteria via an competing risks. Mortality estimates were calculated using cumulative expanded access program (EAP). The NEUF study was a retro- incidence function analysis. To address immortal time bias (i.e., relapse is not spective observational study including both adult and pediatric possible prior to response), landmark analyses were undertaken, comparing patients receiving blinatumomab treatment via an EAP. OS between patients who responded to blinatumomab treatment within the first two cycles and those who did not. Any patient who did not report a response to blinatumomab treatment within two cycles (84 days) was MATERIALS AND METHODS classed as a nonresponder, even if they later had a response. Objective To describe the clinical characteristics and treatment patterns of adult patients with B-cell ALL who received blinatumomab in the EAP, and in RESULTS pre-identified clinically relevant subgroups (i.e., MRD+ Ph−/Ph+ and R/R Patient characteristics Ph−/Ph+ subgroups). Overall, 249 patients were included, of whom 109 were MRD+ (83 Ph− and 26 Ph+) and 140 had a diagnosis of R/R B-cell ALL (106 Patient selection Ph− and 34 Ph+) (Table 1). All patients in the Ph+ subgroup had As described previously, patients treated with blinatumomab in the EAP the BCR-ABL1 translocation confirmed prior to blinatumomab between January 1, 2014, and June 30, 2017, in France, Italy, the Russian initiation (Supplementary Table 1). Owing to missing diagnosis Federation, Spain, and the UK were eligible for inclusion [16]; the sites with data, four additional patients were excluded from these analyses. the largest number of requests were invited to participate in the NEUF In the MRD+ group, most of the patients (71%) had persistent study. Patients were not eligible for inclusion in the study if informed consent was not provided (per local regulations) or if their medical records MRD irrespective of the number of prior salvages and their Ph were not available. Adverse events were reported separately and status. Patients who had no prior salvage therapy (CR1) according to local regulations, as detailed previously [16]. represented 60% and 38% of the Ph− and Ph+ subgroups, respectively. The remaining patients (40% of Ph− and 62% of Ph+) had received at least one prior salvage therapy (CR2+). In Outcome measures CR was defined as ≤5% blasts in the bone marrow, no evidence of the R/R subgroups, 42% of Ph− patients had no prior salvage extramedullary disease, and full recovery of peripheral blood counts (76% relapsed and 24% refractory) and 12% of Ph+ patients had (platelets >100 × 109/L and absolute neutrophil count >1 × 109/L) no prior salvage (50% relapsed and 50% refractory). [9, 16, 17]. CR with partial recovery of peripheral blood counts (CRh) was defined as CR, but with partial recovery of peripheral blood counts Concurrent therapies during blinatumomab treatment (platelets >50 × 109/L and absolute neutrophil count >0.5 × 109/L). CR with Within each group, patients received a median of two cycles of incomplete recovery of peripheral blood counts (CRi) was defined as CR, blinatumomab. In the MRD+ group, four patients (two Ph− and but with incomplete recovery of peripheral blood counts two Ph+) were treated with donor lymphocyte infusion (DLI). In (platelets >100 × 109/L or absolute neutrophil count >1 × 109/L) among patients with R/R B-cell ALL at blinatumomab initiation. the R/R B-cell ALL group, 13 patients (all Ph−) were treated with MRD assessment was undertaken as per local clinical practice using a DLI. Concurrent use of tyrosine kinase inhibitors (TKIs) was technique with a quantifiable sensitivity down to 10−4 assessed by flow documented for 12 patients in the MRD+ Ph+ subgroup and 14 cytometry and polymerase chain reaction. Standardized protocols [18–21] patients in the R/R Ph+ subgroup. Use of TKIs is reported in were available for use in routine clinical practice in the participating Supplementary Fig. 1 and Supplementary Table 2, and comedica- countries, and technique choice was at the discretion of each investigator/ tions of interest are summarized in Supplementary Table 3. site. MRD status was abstracted from each patient’s medical record, and available MRD data were analyzed irrespective of the technique used. Response to blinatumomab treatment Patients categorized as having a complete MRD response were those in CR/CRh/CRi with undetectable MRD within the first cycle or the first two MRD+ group. In patients with evaluable MRD (n = 64), 88% cycles of blinatumomab treatment, depending on how many cycles were (n = 56) achieved an overall MRD response (either a complete required. MRD response was defined as CR/CRh/CRi with low-level MRD response or an MRD response) within the first cycle of nonquantifiable MRD (<10−4/0.01%). Patients with persistent MRD were blinatumomab. Among the 83 patients who were evaluated for those without an MRD response or complete MRD response (quantifiable MRD within two cycles of blinatumomab, 84% (n = 70) had an MRD, ≥10−4/0.01%). Patients with MRD relapse were those in CR/CRh/CRi overall MRD response, representing 91% and 59% of patients in and who had a prior complete MRD response or an MRD response that was the Ph− and Ph+ subgroups, respectively (Fig. 1A). The overall subsequently lost (quantifiable MRD). MRD response did not differ by CR1 or CR2+ status in both the In the MRD+ group, disease-free survival (DFS) was evaluated and Ph− (88% and 91%, respectively) and the Ph+ subgroup (57% and described as the time from blinatumomab initiation to the date of relapse or death in remission, whichever occurred first. 56%, respectively). In the R/R B-cell ALL group, relapse was defined as >5% blasts in the bone marrow or extramedullary relapse after documented CR/CRh/CRi. RFS R/R group. Within the first two cycles of blinatumomab, 54 was estimated for the R/R B-cell ALL group and defined as the time from patients (51%) in the R/R Ph− subgroup achieved CR/CRh/CRi, of achievement of CR/CRh/CRi (best response within the first two cycles) to whom 91% (49/54) achieved CR (Fig. 1B). Among these 54 the date of relapse or death in remission, whichever occurred first. In both patients, 42 had an evaluable MRD assessment within the first two groups, OS was defined as the time from initiation of blinatumomab cycles of blinatumomab and 83% (n = 35) achieved an overall treatment until death from any cause. MRD response (22 had a complete MRD response [52%]; 13 had an Enrolled patients were observed from blinatumomab initiation until MRD response [31%]) (Fig. 1B). death, entry into a clinical trial, the end of follow-up, or the end of the study (December 31, 2017), whichever occurred first. Within the first two cycles of blinatumomab, 14 patients (41%) in The study was approved by the appropriate local institutional review the R/R Ph+ subgroup achieved CR/CRh/CRi and all patients achieved boards/independent ethics committees and was conducted in accordance CR (Fig. 1B). Of these patients, 12 had an evaluable MRD assessment with the principles of the Declaration of Helsinki and Good Clinical Practice (Fig. 1B), and eight of these (67%) achieved either a complete MRD guidelines issued by the International Conference of Harmonisation. response (50%; n = 6) or an MRD response (17%; n = 2). Blood Cancer Journal (2023)13:2 N. Boissel et al. 3 Table 1. Baseline characteristics. MRD+ (N = 109) R/R B-cell ALL (N = 140) Characteristics a All MRD+ (N = 109) Ph− (N = 83) Ph+ (N = 26) a R/R Ph− (N = 106) R/R Ph+a (N = 34) Sex, female, n (%) 45 (41.3) 39 (47.0) 6 (23.1) 50 (47.2) 16 (47.1) Age at blinatumomab 43.0 (27.0–55.0) 35.0 (24.0–56.0) 50.5 (43.0–55.0) 36.5 (24.0–52.0) 51.0 (37.0–64.0) initiation, years, median (IQR) Number of salvage therapies Median (IQR) 0 (0–1) 0 (0–1) 0 (0–2) 1 (0–2) 1 (1–2) Min., max. 0, 4 0, 4 0, 4 0, 5 0, 5 Prior salvage therapy, n (%) n = 77b n = 32c n = 57b n = 26c n = 20b n = 6c n = 64d n = 42e n = 20d n = 14e 0 42 (54.5) 18 (56.2) 35 (61.4) 15 (57.7) 7 (35.0) 3 (50.0) 34 (53.1) 11 (26.2) 2 (10.0) 2 (14.3) 1 21 (27.3) 8 (25.0) 14 (24.6) 6 (23.1) 7 (35.0) 2 (33.3) 13 (20.3) 19 (45.2) 8 (40.0) 6 (42.9) 2+ 14 (18.2) 6 (18.8) 8 (14.0) 5 (19.2) 6 (30.0) 1 (16.7) 17 (26.6) 12 (28.6) 10 (50.0) 6 (42.8) Disease status at blinatumomab initiation, n (%) Full hematologic relapse NE NE NE 64 (60.4) 20 (58.8) Refractory NE NE NE 42 (39.6) 14 (41.2) Persistent MRD 77 (70.6) 57 (68.7) 20 (76.9) NE NE MRD relapse 32 (29.4) 26 (31.3) 6 (23.1) NE NE HSCT before blinatumomab 17 (15.6) 9 (10.8) 8 (30.8) 43 (40.6) 12 (35.3) initiation, n (%) Time between HSCT and 10.2 (3.8–24.9) 9.5 (3.8–21.3) 13.5 (5.4–36.7) 13.0 (7.2–20.0) 10.4 (7.1–20.6) initiation, months, median (IQR) Response before blinatumomab initiation, n (%) CR/CRh/CRi at frontline NE NE NE 84 (79.2) 25 (73.5) therapy Blast count in the bone marrow at blinatumomab initiation, n (%) ≤5 86 (91.5) 65 (91.5) 21 (91.3) 14 (14.6) 2 (7.1) >5 and <10 2 (2.1) 2 (2.8) 0 (0.0) 5 (5.2) 0 (0.0) ≥10 and <50 2 (2.1) 2 (2.8) 0 (0.0) 33 (34.4) 12 (42.9) ≥50 4 (4.3) 2 (2.8) 2 (8.7) 44 (45.8) 14 (50.0) Unknown 15 (NA) 12 (NA) 3 (NA) 10 (NA) 6 (NA) Extramedullary involvement, n (%) Yes NA NA NA 20 (19.2)f 5 (14.7) Central nervous system NA NA NA 4 (3.8) 5 (14.7) Testis NA NA NA 4 (3.8) 0 (0.0) Other NA NA NA 12 (11.5) 0 (0.0) No NA NA NA 84 (80.8) — Unknown NA NA NA 2 (NA) — a Cytogenetics of patients with Ph+ B-cell ALL are presented in Supplementary Table 1. b For the subset of patients who have persistent MRD. c For the subset of patients who are in MRD relapse. d For the subset of patients who are relapsed. e For the subset of patients who are refractory. f Response to blinatumomab was examined in a subgroup of patients with extramedullary involvement. B-cell ALL B-cell acute lymphoblastic leukemia, CR complete remission with full recovery of peripheral blood counts, CRh complete remission with partial recovery of peripheral blood counts, CRi complete remission with incomplete recovery of peripheral blood counts, HSCT hematopoietic stem cell transplantation, IQR interquartile range, max. maximum, min. minimum, MRD minimal residual disease, MRD+ MRD-positive, NA not applicable, NE not estimated, Ph− Philadelphia chromosome-negative, Ph+ Philadelphia chromosome-positive, R/R relapsed/refractory. Patients with extramedullary involvement. In the R/R group, of the Survival outcomes 20 Ph− patients with extramedullary involvement, 10 patients OS and DFS in the MRD+ group. Median OS and median OS (50%) achieved complete hematologic remission with five of these censored at the time of HSCT were not reached (Fig. 2A, B). achieving an MRD response. Among the five Ph+ patients with Median follow-up was 18.5 months (Supplementary Table 4). extramedullary involvement, three achieved complete hematolo- Achieving an overall MRD response in the first two cycles of gic remission, of whom two achieved an MRD response. blinatumomab resulted in better KM estimates for OS at 24 months among MRD responders (71.5%) than among MRD nonresponders Patients with DLI. In the MRD+ group, two of the four patients (57.1%; persistent MRD or MRD relapse) (Supplementary Fig. 2A). treated with DLI had evaluable MRD and both (one Ph− and one Similar results were found in a landmark analysis (Supplementary Ph+) achieved an MRD response. In the Ph− subgroup, 69% Table 5). Median (95% confidence interval [CI]) DFS was 27.6 (n = 9) of patients who received a DLI achieved CR/CRh/CRi (13.0–not estimated [NE]) months (Fig. 2C; Supplementary Table following two cycles of blinatumomab, and five of the six 6), and 33.0 (17.0–NE) months with additional censoring at the evaluable patients (83%) achieved an overall MRD response. time of HSCT (Fig. 2D). DFS estimates at 24 months were better in Blood Cancer Journal (2023)13:2 N. Boissel et al. 4 A MRD response among patients with evaluable MRD in the MRD+ group 100 92.5 90.9 87.5 84.3 80 71.7 72.7 Proportion of patients (%) 62.5 62.7 63.6 58.8 60 45.5 41.2 40 36.4 35.3 25.0 23.5 21.7 20.8 18.2 18.2 20 15.7 12.5 7.5 9.1 0.0 0.0 0.0 0.0 0.0 0.0 0 MRD response MRD response MRD response MRD response MRD response MRD response in first cycle in first two cycles in first cycle in first two cycles in first cycle in first two cycles (n = 64) (n = 83) (n = 53) (n = 66) (n = 11) (n = 17) All MRD+ Ph− Ph+ (N = 109) (N = 83) (N = 26) B Responses in the Ph− and Ph+ subgroups of the R/R group within the first two cycles of blinatumomab treatment 100 83.3 80 Proportion of patients (%) 66.7 60 50.9 52.4 50.0 46.2 41.241.2 40 35.3 33.3 31.0 26.4 19.8 17.6 20 16.7 16.7 5.9 2.8 1.9 2.8 0.0 0.0 0.0 0.0 0 Best hematologic MRD response Best hematologic MRD response response (n = 106) (n = 42)a response (n = 34) (n = 12)b R/R Ph– R/R Ph+ (N = 106) (N = 34) Complete MRD/MRD response Complete MRD response MRD response Persistent MRD MRD relapse CR/CRh/CRi CR CRh CRi Refractory Deceased within two cycles No response data recorded Fig. 1 Response to blinatumomab treatment. A MRD response among patients with evaluable MRD in the MRD+ group. B Responses in the Ph− and Ph+ subgroups of the R/R group within the first two cycles of blinatumomab treatment. aIn total, 106 adult R/R Ph− B-cell ALL patients were included in the study; 54 patients achieved CR/CRh/CRi within the first two cycles of blinatumomab treatment. Of these patients, 42 had evaluable MRD at two cycles. bIn total, 34 adult R/R Ph+ B-cell ALL patients were included in the study; 14 patients achieved CR/CRh/CRi within the first two cycles of blinatumomab treatment. Of these patients, 12 had evaluable MRD at two cycles. B-cell ALL B-cell acute lymphoblastic leukemia, CR complete remission with full recovery of peripheral blood counts, CRh complete remission with partial recovery of peripheral blood counts, CRi complete remission with incomplete recovery of peripheral blood counts, MRD minimal residual disease, MRD+ MRD-positive, Ph− Philadelphia chromosome-negative, Ph+ Philadelphia chromosome-positive, R/R relapsed/refractory. MRD responders than in nonresponders (KM estimates: 61.2% of 25.7 months in the Ph− subgroup (median follow-up, 18.6 months) MRD responders vs 36.9% of MRD nonresponders; Supplementary and was not reached in the Ph+ subgroup (median follow-up, Fig. 3). 16.2 months) (Supplementary Table 6). In the Ph− subgroup, In both Ph− and Ph+ subgroups, the KM estimates for OS and better outcomes were observed in the CR1 subgroup than in the DFS at 24 months were consistent with those in the overall CR2+ subgroup (median OS: NE versus 16.98 months [Fig. 2E]; MRD+ group (Supplementary Fig. 2A; Supplementary Fig. 3; median DFS: 32.98 versus 11.34 months). The KM estimates for OS Supplementary Table 4; Supplementary Table 5). DFS was and DFS at 24 months are shown in Supplementary Figs. 2A and 3. Blood Cancer Journal (2023)13:2 N. Boissel et al. 5 A B 1.0 1.0 0.8 0.8 Survival probability Survival probability 0.6 0.6 0.4 0.4 0.2 0.2 Censored Censored 0 Median OS: NE 0 Median OS: NE 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Time (months) At risk 107 102 96 82 66 50 38 28 23 17 12 6 0 At risk 108 73 39 31 24 19 14 10 6 6 5 3 0 Median Median Patients Event Censored survival 95% CI Patients Event Censored survival 95% CI 107 33 74 NE 24.72–NE 108 9 99 NE NE C D 1.0 1.0 0.8 0.8 Survival probability 0.6 Survival probability 0.6 0.4 0.4 0.2 0.2 Censored Censored 0 Median DFS: 27.6 (min., max.: 0.4, 33.0) months 0 Median DFS: 33.0 (min., max.: 0.4, 33.0) months 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Time (months) At risk 108 99 88 65 54 43 31 22 18 14 10 5 0 At risk 108 69 35 25 21 18 13 9 6 5 4 2 0 Median Median Patients Event Censored survival 95% CI Patients Event Censored survival 95% CI 108 46 62 27.64 12.95–NE 108 20 88 32.98 16.98–NE E 1.0 0.8 Survival probability 0.6 Median OS (min., max.), months 0.4 CR1 NE (6.2, 17.5) CR1, HSCT censoring NE (14.8, 14.8) 0.2 Censored CR2+ 16.98 (0.4, 27.9) 0 CR2+, HSCT censoring 16.98 (0.4, 17.0) 0 3 6 9 12 15 18 21 24 27 30 33 36 At risk Time (months) CR1 49 49 49 42 32 24 20 17 15 11 10 5 0 CR1, HSCT censoring 49 36 20 16 13 9 7 6 5 5 5 3 0 CR2+ 28 25 23 21 15 10 6 4 4 2 1 1 0 CR2+, HSCT censoring 29 12 7 6 2 2 0 Median Patients Event Censored survival 95% CI CR1 49 12 37 NE NE CR1, HSCT censoring 49 1 48 NE NE CR2+ 28 14 14 16.98 11.38–27.87 CR2+, HSCT censoring 29 6 23 16.98 9.11–16.98 Fig. 2 KM analysis of OS and DFS in the MRD+ group. A OS. B OS with additional censoring at the time of HSCT. C DFS. D DFS with additional censoring at the time of HSCT. E OS by CR1/CR2+ status with or without additional censoring at the time of HSCT. In the OS analysis, two adult patients were excluded from the crude analysis and one patient was excluded from the HSCT-censored analysis because of missing data on the date of the event. In the DFS analysis, one patient was excluded because of missing data (dates). For OS and DFS, patients were censored if they were alive at the end of the study or they were lost to follow-up. CI confidence interval, CR1 defined patients who reached complete remission after first induction therapy, CR2+ defined patients who reached complete remission after one or more salvage therapies for relapsed or refractory disease, DFS disease-free survival, HSCT hematopoietic stem cell transplantation, KM Kaplan–Meier, max. maximum, min. minimum, MRD+ minimal residual disease-positive, NE not estimable, OS overall survival. Blood Cancer Journal (2023)13:2 N. Boissel et al. 6 OS and RFS in the R/R group. In the Ph− subgroup, median (95% reported to date. The real-world effectiveness of blinatumomab in CI) OS was 12.2 (7.3–24.2) months (Fig. 3A; Supplementary Table adults with MRD+ or R/R ALL was comparable to that reported in 4), and 9.5 (7.1–24.2) months when censoring for HSCT (Fig. 3B). other clinical and real-world studies [2, 3, 6, 9–15]. Median (95% CI) RFS was 11.0 (8.2–15.4) months with and without In the MRD+ group, over half of patients were in CR1 and 84% additional censoring at the time of HSCT (Fig. 3C, D; Supplemen- of patients with an evaluable MRD achieved an overall MRD tary Table 6). The KM estimate (95% CI) for RFS at 24 months was response within the first two cycles of blinatumomab therapy. 33.1% (19.0–47.8%) overall (Supplementary Table 6), 35.0% in MRD Moreover, the MRD+ group included more than two-thirds of responders, and 28.6% in MRD nonresponders (Supplementary patients with persistent MRD prior to initiating blinatumomab Fig. 4). KM estimates for OS at 24 months were better among therapy. The overall results in the MRD+ group align with responders (CR/CRh/CRi or MRD) versus nonresponders, in previously reported efficacy data from clinical and real-world patients with a prior HSCT versus no prior HSCT, and in patients studies. In the Phase 2 clinical trial, 78% of patients achieved a with bone marrow blasts <50% versus ≥50% at blinatumomab complete MRD response [3]. In the FRENCH-CYTO study, 89% of initiation (Supplementary Fig. 2B). In the Ph+ subgroup, median the MRD+ patients achieved a complete MRD response following (95% CI) OS was 16.3 (5.3–NE) months (Fig. 3E), and 16.3 (5.3–16.3) blinatumomab [13]. Crucially, the NEUF study shows that survival months with additional censoring at the time of HSCT (Fig. 3F). KM outcomes were improved in patients who did versus did not have estimates for OS at 24 months were 56.6% in responders and an MRD response, and in patients in the CR1 versus CR2+ 46.4% in nonresponders (Supplementary Fig. 2C). Median RFS was subgroup, in line with earlier findings from the Phase 2 trial [6]. 6.7 months in analyses with or without additional censoring at the Nonrelapse mortality at 12 months was 10% in the MRD+ group. time of HSCT (Fig. 3G, H; Supplementary Table 6). The KM estimate In the R/R Ph− subgroup, over half of patients achieved CR/ (95% CI) for RFS at 24 months was 21.2% (4.0–47.3%) (Supple- CRh/CRi and over one-third proceeded to HSCT, in line with the mentary Table 6). results of the Phase 3 trial in which nearly half of patients had also received blinatumomab in their first salvage [9, 10]. The transplant OS and RFS in R/R patients with DLI. In the Ph− subgroup of realization rate was considerably higher in patients in the NEUF patients who received a DLI, four out of 13 died from any cause. At study than in the Phase 3 clinical trial. The relatively short median 12 months and 18 months, OS (95% CI) was 76.2% (42.7–91.7%) and interval from achieving CR/CRh/CRi to HSCT of 4.6 months among 66.6% (33.1–86.1%), respectively. Of the nine patients with CR/CRh/ patients who did not receive other cytotoxic therapy indicates that CRi, one patient died from any cause and three patients relapsed. At blinatumomab is being used as a bridge to transplantation. 12 months and 18 months, RFS (95% CI) was 51.9% (16.4–78.8%). Importantly, patients who had an HSCT before blinatumomab initiation as well as patients who achieved CR/CRh/CRi and/or an Outcomes following blinatumomab treatment MRD response following blinatumomab treatment had an In the MRD+ group, 74 patients (68%) receiving blinatumomab improved survival result compared with patients who did not. proceeded to HSCT (Supplementary Table 7). Of these, 66% Moreover, given the good results when censoring for HSCT, (n = 49) achieved an MRD response before transplant. In patients blinatumomab could be considered to be a valuable option also with an MRD response following blinatumomab who did not have for older patients unfit for transplantation. Despite some any cytotoxic therapy (n = 43) between blinatumomab and differences in patient characteristics and outcomes, the data of transplant (Supplementary Table 7), the median (95% CI) time the NEUF study align overall with the literature [13–15]. from achieving an MRD response to HSCT was 2.3 (1.6–9.1) In the R/R Ph+ subgroup, over 40% of patients achieved CR/ months. CRh/CRi within two cycles of blinatumomab initiation and over In the R/R group, of the Ph− patients who were in CR/CRh/CRi, two-thirds of these patients with available MRD data achieved 43 (41%) proceeded to HSCT (Supplementary Table 7), among an MRD response. Most patients in the R/R Ph+ subgroup had whom 33 (77%) achieved CR/CRh/CRi before transplant. Of these at least one prior salvage therapy. Over one-third of patients 33 patients, 29 achieved CR/CRh/CRi and proceeded to HSCT achieved CR/CRh/CRi and proceeded to allogeneic HSCT with- without additional cytotoxic therapy. In this subgroup, median out further therapy. This was similar to results reported in a (95% CI) time from achieving CR/CRh/CRi to HSCT was 4.6 (2.2–NE) Phase 2 trial of patients with R/R Ph+ , in which 36% of patients months. achieved CR/CRh/CRi within two cycles of blinatumomab Among the Ph+ patients in the R/R group who were in CR/CRh/ initiation and 88% of these patients achieved an MRD response CRi, 11 (32%) proceeded to HSCT following blinatumomab [12]. As expected, the Ph+ subgroup had slightly worse treatment (Supplementary Table 7). Of these, six (55%) achieved outcomes than the Ph− subgroup. Patients with Ph+ B-cell CR/CRh/CRi after blinatumomab initiation and all were treated ALL are considered to be high risk owing to their cytogenetic with additional cytotoxic therapy before HSCT. Median time to profile and the limited MRD response to treatment [22, 23]. With HSCT was not reached. regard to the improvement of the MRD response induced by blinatumomab in patients with Ph+ B-cell ALL, its efficacy in Nonrelapse mortality after HSCT patients who were newly diagnosed with Ph+ B-cell ALL was In the MRD+ group, mortality following HSCT was evaluable in 56 reported in the D-ALBA study [23], in which 60% of patients patients. Nonrelapse mortality (95% CI) at 12 months was 10.1% achieved a molecular response following treatment with (4.3–23.8%; Table 2). In the Ph− and Ph+ subgroups, 12-month dasatinib and two cycles of blinatumomab. Molecular response mortality (95% CI) was 9.0% (3.3–24.4%) and 18.1% (3.7–90.0%), rates further increased with additional cycles of blinatumomab. respectively. As proposed by Puzzolo et al, the host immune system may In the R/R group, mortality following HSCT was evaluable in 29 contribute to this effect of blinatumomab in this setting [24]. Ph− patients, and nonrelapse mortality (95% CI) at 12 months was This may explain the encouraging results obtained in patients 19.3% (9.3–40.4%). In the Ph+ subgroup, mortality following HSCT treated with DLI. was evaluable in six patients, and nonrelapse mortality (95% CI) In a proportion of patients with extramedullary involvement following HSCT at 12 months was 15.4% (2.9–84.6%) (Table 2). included in the NEUF study, blinatumomab elicited a response regardless of Ph status, and this response was consistent with the cytomorphological response of each Ph− or Ph+ subgroup; this is DISCUSSION one of the first reports on the effect of blinatumomab in this subset of The NEUF study describes the largest documented European cohort patients. Overall, these results highlight the real-world effectiveness of of patients treated with blinatumomab in real-world clinical practice blinatumomab in different subgroups of patients with B-cell ALL. Blood Cancer Journal (2023)13:2 N. Boissel et al. 7 A B 1.0 1.0 0.8 0.8 Survival probability Survival probability 0.6 0.6 0.4 0.4 0.2 0.2 Censored Censored 0 Median OS: 12.2 (min., max.: 0.2, 24.6) months 0 Median OS: 9.5 (min., max.: 0.2, 24.2) months 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 Time (months) Time (months) At risk 102 83 65 44 34 26 16 13 10 4 2 0 At risk 102 70 36 20 17 12 8 4 2 1 1 0 Median Median Patients Event Censored survival 95% CI Patients Event Censored survival 95% CI 102 55 47 12.16 7.25–24.20 102 39 63 9.54 7.11–24.20 C D 1.0 1.0 0.8 0.8 Survival probability Survival probability 0.6 0.6 0.4 0.4 0.2 0.2 Censored Censored 0 Median RFS: 11.0 (min., max.: 0.0, 15.4) months 0 Median RFS: 11.0 (min., max.: 0.0, 15.4) months 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30 Time (months) Time (months) At risk 54 43 33 25 18 11 6 5 5 2 0 At risk 54 21 14 11 7 4 2 1 1 1 0 Median Median Patients Event Censored survival 95% CI Patients Event Censored survival 95% CI 54 30 24 10.95 8.23–15.38 54 15 39 10.95 10.00–NE E F 1.0 1.0 0.8 0.8 Survival probability Survival probability 0.6 0.6 0.4 0.4 0.2 0.2 Censored Censored 0 Median OS: 16.3 (IQR: 4.6–NE) months 0 Median OS: 16.3 (IQR: 4.6–16.3) months 0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 Time (months) Time (months) At risk 31 24 18 15 11 6 5 3 2 0 At risk 31 23 13 7 4 1 0 Median Median Patients Event Censored survival 95% CI Patients Event Censored survival 95% CI 31 15 16 16.33 5.31–NE 31 13 18 16.33 5.31–16.33 G H 1.0 1.0 0.8 0.8 Survival probability Survival probability 0.6 0.6 0.4 0.4 0.2 0.2 Censored Censored 0 Median RFS: 6.7 (IQR: 3.3–18.2) months 0 Median RFS: 6.7 (IQR: 3.3–8.6) months 0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 Time (months) Time (months) At risk 14 11 7 4 4 3 3 2 1 0 At risk 14 10 6 1 1 0 Median Median Patients Event Censored survival 95% CI Patients Event Censored survival 95% CI 14 10 4 6.66 1.57–18.16 14 9 5 6.66 1.57–8.62 The limitations of this study merit consideration and have been with the largest proportion of expanded access requests across detailed previously [16]. Individuals enrolled in an EAP may not be the selected countries were invited to participate in the NEUF representative of the wider population of patients with B-cell ALL study. Of those, 51 sites participated. Finally, a small proportion of receiving blinatumomab treatment. An additional limitation of the patients in the MRD+ group demonstrated bone marrow blasts study was a potential patient selection bias given that only sites >5%; this may indicate that clinicians enrolled patients with an Blood Cancer Journal (2023)13:2 N. Boissel et al. 8 Fig. 3 KM analysis of OS and RFS in the R/R Ph− and R/R Ph+ subgroups. A Time-to-event analysis for OS in the R/R Ph− subgroup. B OS with additional censoring at the time of HSCT in the R/R Ph− subgroup. C Time-to-event analysis for RFS in the R/R Ph− subgroup. D RFS with additional censoring at the time of HSCT in the R/R Ph− subgroup. E Time-to-event analysis for OS in the R/R Ph+ subgroup. F OS with additional censoring at the time of HSCT in the R/R Ph+ subgroup. G Time-to-event analysis for RFS in the R/R Ph+ subgroup. H RFS with additional censoring at the time of HSCT in the R/R Ph+ subgroup. In the R/R Ph− subgroup, four patients were excluded from the analysis owing to missing data. In the R/R Ph+ subgroup, three patients were excluded from the analysis because of missing data. For OS and RFS, patients were censored if they were alive at the end of the study or they were lost to follow-up. CI confidence interval, HSCT hematopoietic stem cell transplantation, IQR interquartile range, max. maximum, KM Kaplan–Meier, min. minimum, NE not estimable, OS overall survival, Ph − Philadelphia chromosome-negative, Ph+ Philadelphia chromosome-positive, R/R relapsed/refractory, RFS relapse-free survival. Table 2. Mortality after allogeneic HSCT by B-cell ALL diagnosis. MRD+ R/R B-cell ALL All MRD+ (n = 56) Ph− (n = 50) a Ph+ (n = 6) Ph−b (n = 29) Ph+c (n = 6) d Mortality following HSCT, % (95% CI) 3 months 5.5 (1.9–16.3) 4.1 (1.1–15.2) 18.1 (3.7–90.0) 10.7 (3.4–34.0) 15.4 (2.8–84.6) 6 months 5.5 (1.9–16.3) 4.1 (1.1–15.2) 18.1 (3.7–90.0) 14.8 (5.8–37.4) 15.4 (2.8–84.6) 12 months 10.1 (4.3–23.8) 9.0 (3.3–24.4) 18.1 (3.7–90.0) 19.3 (9.3–40.4) 15.4 (2.9–84.6) Events, n (%) Nonrelapse deaths 6 (11) 5 (10) 1 (16.7) 5 (17.2) 1 (16.7) Relapse 11 (20) 11 (22) 0 (0.0) 8 (27.6) 1 (16.7) Death due to undocumented 3 (5) 3 (6) 0 (0.0) 2 (6.9) 0 (0.0) relapse Death due to unknown causes 1 (2) 1 (2) 0 (0.0) 0 (0.0) 0 (0.0) Patients alive without relapse 34 (61) 29 (58) 5 (83.3) 14 (48.3) 4 (66.7) a One patient excluded owing to missing data on date of event. b Patients achieved CR/CRh/CRi following blinatumomab treatment and proceeded to HSCT without any intervening cytotoxic therapy. c Patients achieved CR/CRh/CRi following blinatumomab treatment and were treated with other cytotoxic therapy and then proceeded to HSCT (all R/R Ph+ patients who proceeded to transplantation were treated with additional cytotoxic therapy following blinatumomab). d Mortality not due to disease relapse is evaluated by the cumulative incidence function, with relapse and death due to undocumented relapse as competing events. B-cell ALL B-cell acute lymphoblastic leukemia, CI confidence interval, CR complete remission with full recovery of peripheral blood counts, CRh complete remission with partial recovery of peripheral blood counts, CRi complete remission with incomplete recovery of peripheral blood counts, HSCT hematopoietic stem cell transplantation, MRD+ minimal residual disease-positive, Ph− Philadelphia chromosome-negative, Ph+ Philadelphia chromosome-positive, R/R relapsed/refractory. All patients were treated with additional immunosuppressive therapy between blinatumomab and allogenic HSCT. advanced disease or that the patient’s disease had progressed by 6. Gökbuget N, Zugmaier G, Dombret H, Stein A, Bonifacio M, Graux C, et al. Curative the time they received blinatumomab. outcomes following blinatumomab in adults with minimal residual disease B-cell In conclusion, these results from the largest European real-word precursor acute lymphoblastic leukemia. 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