Up-front blinatumomab improves MRD clearance and outcome in adult Ph^– B-lineage ALL: the GIMEMA LAL2317 phase 2 study Free

Acute lymphoblastic leukemia (ALL) is the prototypical chemotherapy-curable neoplasm, with outstanding cure rates reported in children with Philadelphia chromosome/BCR::ABL1 rearrangement–negative (Ph^–) ALL.¹ In adults, although most patients achieve complete remission (CR), the risk of relapse can exceed 20% to 30%, and salvage results are poor, owing to an unfavorable risk profile and lower compliance to intensive pediatric-like regimens and allogeneic hematopoietic stem cell transplantation (allo-HSCT).² Recent large multicentric adult trials adopting a risk-oriented postinduction strategy have reported survival rates between 50% and 70%,^3-11 with variations across age and risk groups. Efforts to improve are underway using novel immunotherapeutic agents up-front, after demonstration of efficacy at resistance/relapse (R/R).^12,13 

Blinatumomab is a bispecific CD3 × CD19 antibody construct that bridges together normal CD3⁺ T cells and CD19⁺ leukemic B cells, thereby eliciting the activation and expansion of host cytotoxic T effectors.¹⁴ After successful trials in R/R and minimal/measurable residual disease–positive (MRD⁺) B-lineage ALL (B-ALL),^15-22 several studies were implemented to assess blinatumomab as frontline monotherapy for older patients with ALL or in combination with chemotherapy in adult ALL.^23-29 

The Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) designed a prospective phase 2 study consisting of a chemotherapy-blinatumomab sequence for untreated adults (aged 18-65 years) with Ph^– CD19⁺ B-ALL, which is the most common ALL subset. Briefly, two 4-week continuous IV infusion blinatumomab courses were administered after cycles 3 and 6 of a chemotherapy backbone similar to the previous GIMEMA LAL1913 study.⁹ Before receiving blinatumomab, remission patients were risk stratified for risk-oriented allo-HSCT or standard chemotherapy using the GIMEMA risk model integrating clinical characteristics and postinduction MRD. The primary study end point was the rate of MRD negativity after blinatumomab 1, anticipating an improved outcome regardless of the assigned risk-oriented treatment,^30-33 whereas the secondary end points concerned the evaluation of toxicity and outcome in distinct risk categories. Here, we report the results of this study.

Study patients had untreated Ph^– CD19⁺ B-ALL, were aged 18 to 65 years, and signed an informed consent form according to the Declaration of Helsinki (1975; revised 2008). Protocol LAL2317 was sponsored by GIMEMA, approved by the Ethics Committees of all participating Institutions, and registered at www.ClinicalTrials.gov (identifier: NCT03367299; supplemental Methods and supplemental Table 2, available on the Blood website).

Study eligibility and screening procedures, chemotherapy elements, supportive measures, MRD study methods, risk classification, and risk-oriented strategy were the same as in GIMEMA LAL1913 trial (Figure 1; supplemental Methods).⁹ Induction, consolidation, and reinduction therapy consisted of 8 chemotherapy blocks (age adapted for patients aged >55 years), intrathecal central nervous system (CNS) prophylaxis, and 2 blinatumomab courses. The treatment plan was completed either by risk-oriented allo-HSCT performed after blinatumomab 1 or by 2-year long maintenance chemotherapy. Patients eligible for but unable to receive an HSCT continued with protocol chemotherapy.

Blinatumomab, provided by Amgen Europe Inc, was administered at 28 μg/d as continuous IV infusion on days 1 to 28 after chemotherapy cycles 3 and 6. The interval between any chemotherapy and blinatumomab cycle was 21 to 28 days, provided any prior toxicity had resolved (grade <2), and the neutrophil and platelet counts were >1.0 × 10⁹/L and >75 × 10⁹/L, respectively. Patients were hospitalized for a minimum of 3 and 2 days at blinatumomab 1 and blinatumomab 2, respectively. On day –1, a diagnostic and medicated lumbar puncture was performed to rule out CNS involvement. Patients were premedicated with levetiracetam 500 mg twice daily orally until the end of treatment for antiepileptic prophylaxis and received IV dexamethasone 20 mg 1 hour before the start of blinatumomab to prevent inflammatory reactions and cytokine release syndrome. In case of blinatumomab-related acute adverse events (AEs) of grade ≥2, dose modifications and toxicity management were according to protocol recommendations (supplemental Methods). Permanent blinatumomab discontinuation was mandatory in case of >1 seizure episodes, grade 4 CNS toxicity, or CNS toxicity leading to treatment interruption requiring >1 week to resolve to grade $≤$1.

MRD was assessed at EuroMRD-certified laboratories in Rome, Palermo, and Bergamo according to standardized methods,^34,35 in line with the central handling procedures of the GIMEMA protocols.⁹ Fresh marrow samples were obtained at diagnosis for the generation of molecular probes with a sensitivity of ≥10^–4, recognizing patient-specific immunoglobulin and T-receptor gene rearrangements or fusion genes (ie, TCF3::PBX1, KMT2A rearrangements, and ETV6::RUNX1), according to the EuroMRD guidelines. Cases without suitable molecular probes were evaluated through sensitive multiparametric flow cytometry (MFC) detecting B-ALL phenotypes, using an 8-color strategy, with a minimum sensitivity of 10^–4, and acquiring 1 × 10⁶ cells. MRD was assessed at the end of cycles 1 (time point 1 [TP1]), 3 (TP2), blinatumomab 1 (TP3), 6 (TP4), and 7 (TP5) and was defined as negative when undetectable.

Study patients were stratified as standard, high, and very high risk (SR, HR, and VHR). SR patients had no risk features. HR patients exhibited a pro-B phenotype, a white blood cell (WBC) count of >30 × 10⁹/L to 100 × 10⁹/L, or had achieved a late CR, that is, after cycle 2. VHR patients had a WBC count of >100 × 10⁹/L or expressed an adverse genetics/cytogenetics (supplemental Methods); the BCR::ABL1-like predictor³⁶ was a risk factor for prognostic analysis but did not affect the therapy-oriented risk definition. CR patients were risk restratified through MRD for risk-oriented therapy (supplemental Table 3). According to the study multipoint MRD risk stratification model (S-MRD), patients with low positive (<10^–4) or undetectable TP2 to TP3 MRD, and undetectable TP4 MRD were classified as S-MRD negative (S-MRD⁻), whereas those with TP2 to TP3 MRD ≥10^–4 or any detectable TP4 MRD were classified as S-MRD positive (S-MRD⁺). Single MRD TPs were considered in relation to the study objectives and prognostic analyses.

According to study design, an allo-HSCT was the default choice for VHR patients, whereas this indication depended on MRD status in SR and HR patients. Therefore, the standard consolidation/maintenance group comprised all S-MRD⁻ SR/HR patients and SR patients with unknown MRD; the allo-HSCT group comprised all VHR patients, S-MRD⁺ SR/HR patients, and HR patients with unknown MRD. VHR and TP2 MRD⁺ SR/HR patients were eligible for an early HSCT after blinatumomab 1. To expedite this procedure, the search for a family-related or unrelated HSCT donor was initiated at diagnosis. All types of stem cell sources and conditioning regimens were permitted, in keeping with national and international guidelines, patient characteristics, and decisions of responsible physicians.

Outcome after induction chemotherapy was CR, resistance, or early death. Refractory patients not in CR after course 2 went off study but were included in the overall survival (OS) analysis. CR was defined as the disappearance of all signs and symptoms attributable to ALL in a patient with neutrophils >1 × 10⁹/L, platelets >100 × 10⁹/L, and a normocellular or regenerating bone marrow with blasts <5%. A recurrence was defined as the reappearance of >5% marrow leukemic cells and/or a documented extramedullary involvement. OS was calculated from diagnosis to death by any cause, disease-free survival (DFS) from CR to relapse in any site or death in CR by any cause, and event-free survival (EFS) from study entry until failure to achieve CR, relapse, or death, whichever occurred first. Treatment-related toxicity was evaluated according to the Common Toxicity Criteria for Adverse Events, version 4.0.

The sample size for the primary study objective was calculated using the methods for an exact single-stage phase 2 design³⁷ to detect a significant increase in the rate of TP3 MRD negativity after blinatumomab 1 compared with postchemotherapy TP2 MRD. Assuming from prior studies an early MRD negativity after standard induction/consolidation at week 10 of ∼60% (P0), the number of patients required to evaluate an increase of MRD negativity from 60% (P0) to 75% (P1), with α of 0.05 and power (1 − β) of 0.90, was 85. Considering that at least 85% of observed patients would be in CR with ∼75% of them evaluable for MRD analysis and an expected loss of 10% of patients, the total number of patients to be enrolled was 149. The secondary objectives were CR rate, OS, EFS, DFS, cumulative incidence of relapse (CIR), treatment-related mortality (TRM), nonrelapse mortality (NRM), MRD response, and serious AEs overall and by patient age, risk class, and treatment subset.

As previously reported,⁹ patients’ characteristics were summarized by crosstabulations for categorical variables or quantiles for continuous variables. Nonparametric tests were performed for comparisons among groups (χ² and Fisher exact tests for categorical variables and Mann-Whitney and Kruskal-Wallis tests for continuous variables). Three-year OS, EFS, and DFS, with 95% confidence intervals, were estimated using the Kaplan-Meier product limit estimator and compared using the log-rank test. The Cox regression model was used in univariate and multivariate analysis, reporting hazard ratios and 95% confidence intervals. Simon-Makuch plotting was used to assess the time-dependent effects of HSCT. CIR and TRM were estimated using the cumulative incidence method, considering death in CR (CIR analysis) or relapse (TRM/NRM analysis) as a competing event. The Gray test was applied to test the differences between subgroups. All tests were 2-sided, accepting P value <.05 as indicating a statistically significant difference. All analyses were performed by the GIMEMA data center following the intention-to-treat (ITT) principle using R software. Study data were collected and managed using REDCap electronic data capture tools hosted at the GIMEMA Foundation.

Trial database was locked in October 2023. All 149 patients enrolled between June 2018 and June 2020 were analyzed (Figure 2; Table 1). The median patient age was 41 years (range, 18-65), and 19% were aged >55 years. Sixteen and 10 patients had a WBC count of >30 × 10⁹/L to 100 × 10⁹/L and >100 ×10⁹/L, respectively; 23 had a pro-B phenotype; and 12 had CNS involvement. Fourteen patients expressed a KMT2A/11q23 rearrangement, 12 had other adverse karyotypes, 10 displayed a TP53 mutation, 5 had t(1;19)/TCF3::PBX1⁺ ALL, and 6 had hyperdiploid ALL. Thirty-one of 111 evaluable patients displayed a Ph-like ALL signature (27.9%). Altogether, 57% of patients were SR, 19% HR, and 23% VHR. Eighteen patients with Ph-like ALL were classified as SR, 7 as HR, and 6 as VHR.

CR was achieved after 1 (n = 122) or 2 induction courses (n = 10) in 132 patients (89%). The incidence of early deaths and refractory ALL was 8.1% (n = 12) and 3.4% (n = 5), respectively. The CR rate was higher in patients aged 18 to 55 years (94%, 18-40 years; 92%, 41-55 years; 68%, >55 years; P = .002), due to a higher induction death rate in patients aged >55 years (4%, 18-55 years; 25%, >55 years; P = .004). None of the 5 refractory patients had KMT2A⁺ ALL, 4 carried a TP53 mutation, 2 expressed a Ph-like ALL gene signature, and 2 were alive after salvage therapy.

Sensitive molecular markers were available for 111 patients (immunoglobulin/T-receptor gene rearrangements, n = 98; fusion genes, n = 13), and 24 further patients could be monitored by MFC, resulting in a total of 135 MRD-evaluable patients. MRD was <10^–4 in 53% of 127 evaluable patients (40% MRD negative [MRD^–]) at the end of TP1 and in 70% of 122 patients (57% MRD⁻) at TP2 before blinatumomab 1. Considering MRD risk stratification, 82 patients were classified as S-MRD⁻ (66.7%) and 41 as S-MRD⁺ (33.3%), with similar results among molecular and MFC analysis. According to the combined risk model, the HR group eligible for allo-HSCT (n = 60) consisted of 31 VHR patients (S-MRD⁺, n = 14; S-MRD^–, n = 14; and MRD unknown, n = 3) and 29 S-MRD⁺ patients (SR, n = 14; HR, n = 15; 24 with TP2 MRD), whereas the SR group eligible for postconsolidation maintenance chemotherapy (n = 72) consisted of 66 S-MRD⁻ patients (SR, n = 58; HR, n = 8) and 6 SR patients with unknown MRD. Regarding Ph-like ALL, 14 patients were assigned to allo-HSCT (S-MRD⁺, n = 10; received transplant, n = 6) and 13 to maintenance chemotherapy. TP3 MRD results were the primary study end point and are detailed below.

As depicted in Figure 2, the allo-HSCT realization rate among 60 eligible patients was 51.6% (n = 31) at a median of 6.4 months from CR (range, 5.3-7.2; allotransplantation details in supplemental Table 4). All 31 HSCT patients received blinatumomab 1 before HSCT. Of the remaining 29 patients, 28 received chemotherapy, 21 blinatumomab 1 (72.4%), and 8 blinatumomab 2. Pretransplantation relapse (n = 15), treatment toxicity, refusal, and protocol infringement accounted for HSCT exclusions. The chemotherapy realization rate among 72 eligible patients was 88%. Seventy patients received blinatumomab 1, 54 received blinatumomab 2, 47 started maintenance, and 6 received an allograft because of poor chemotherapy tolerance and/or at physician’s discretion.

One hundred twenty-two CR patients received blinatumomab 1 (92.4%) for a median of 28 infusion days (range, 1-28), 110 underwent a TP3 MRD assessment, and 109 had evaluable paired TP2 and TP3 MRD marrow samples. With 22 of 30 MRD-resistant patients converting to MRD negativity after blinatumomab (73%), the MRD negativity rate increased from 72% to 93% (P < .001), fulfilling the primary trial end point (Table 2). TP3 MRD negativity was unrelated to age but was less likely in VHR patients (P = .02). All 7 MRD⁺ patients with Ph-like ALL converted to an MRD⁻ status. The second blinatumomab course was administered to 62 patients after chemotherapy cycle 6 and TP4 MRD analysis (n = 70), followed by chemotherapy cycle 7 and TP5 MRD study (n = 60). At these late TPs, 94% and 95% of evaluable patients were MRD⁻. Eight patients displayed post-blinatumomab MRD (7%), including a single TP2 MRD⁻ patient with TCF3::PBX1⁺ ALL.

With all study patients off therapy at a median follow-up of 38.1 months (range, 0.5-62.8), 92 patients were alive in first complete remission (CR1; 61.7%), 15 were alive after R/R, 8 died in CR, and 22 died of leukemia or treatment complications at R/R. The median OS, EFS, and DFS were not reached and were projected at 71%, 59%, and 65% at 3 years (Figure 3A-C), respectively, with higher figures in the 18 to 40 years (77%, 66%, and 70%) and 41 to 55 years age cohorts (72%, 59%, and 61%) than in those aged >55 years (51%, 41%, and 51%). Focusing on the main study objective, in patients receiving blinatumomab 1 (n = 122), the 3-year OS and DFS were 82% and 68%, respectively (Figure 3D-E), without any detectable difference according to the post-blinatumomab MRD status (Figure 3F). Because in prior experiences an early MRD response <10^–4 at week 10/TP2 was the strongest predictor of survival,^9,35 we assessed the combined clinical effects of pre- and post-blinatumomab MRD status. Mimicking historical experiences, in blinatumomab-treated patients, the 3-year OS was 89% for the TP2 MRD⁻ group (n = 85) compared with 49% for the 37 TP2 MRD⁺ patients (Figure 4A; P = .0002), although most of the latter turned MRD⁻ after blinatumomab 1 (n = 30 evaluable; Table 2). The joint TP2/TP3 MRD analysis confirmed a significantly worse outlook, with more relapses and shorter DFS in 23 TP2 MRD⁺/TP3 MRD⁻ patients compared with 78 TP2/TP3 MRD⁻ patients (Figure 4B; supplemental Figure 5 for DFS and CIR).

Overall, by ITT, the 3-year OS rates of patients assigned to standard chemotherapy or HSCT were 91% and 59%, respectively (P = .0029; Figure 4C), and 92% and 65% in blinatumomab recipients (Figure 4D). In the allo-HSCT cohort, a time-dependent analysis confirmed the therapeutic advantage associated with this procedure compared with no HSCT (Figure 4E; 3-year survival for HSCT, 69%; for no HSCT, 38%; P = .0324; supplemental Figure 6, corresponding DFS graphs; supplemental Figure 7, same analysis for blinatumomab-treated patients). Treatment failures were due to refractory ALL (n = 5), induction death (n = 12), ALL recurrence (n = 32), and NRM (n = 8; Figure 4F). The recurrence rate was 35% (n = 21) in the allo-HSCT group (19.3%, transplant recipients) and 15.2% (n = 11) in the chemotherapy group. The median time to relapse was 10.5 months (range, 1.5-34.3). Sites of relapse were the bone marrow (n = 22), combined marrow and CNS (n = 4), isolated CNS (n = 1), and other extramedullary sites (n = 5). The median survival from the date of R/R was 5.92 months, with 2 refractory and 13 relapsed patients alive at the time of this analysis. The incidence of NRM was 6.9% in the chemotherapy group, 5% in the allo-HSCT group, and 11% in HSCT recipients (including 6 who received graft from the chemotherapy group).

The salient risk features of all 37 TP2 MRD⁺ patients (supplemental Table 8) were a high incidence of KMT2A rearrangements (n = 6), Ph-like ALL (n = 9), adverse karyotype (n = 3), IKZF1 deletion with or without additional copy number alterations (CNA, n = 9), and other adverse molecular rearrangements/aberrancies involving CLRF2 (n = 2), JAK2 (n = 2), MEF2D (n = 2), ABL1 (n = 1), TP53 (n = 1), and HLF::TCF3 (n = 1). Moreover, the 8 patients with blinatumomab-resistant MRD (7 TP2 MRD⁺ and 1 MRD⁻) were also more likely to display similar features, such as a non-SR profile (VHR, n = 5; HR, n = 1), a KMT2A rearrangement (n = 4), extensive CNA aberrancies (n = 2 [of 2] evaluable), and a WBC count >30 × 10⁹/L (n = 3). Of note, the relapse risk among TP2 MRD⁺ patients was 23.8% after allo-HSCT (n = 5 [of 21]) and 60% without HSCT (n = 10 [of 16]). In TP3 MRD-evaluable patients, posttransplantation relapse occurred in 5 of 23 MRD⁻ patients (21.7%; KMT2A⁺ ALL, n = 1; Ph-like ALL, n = 3; and CLRF2⁺ ALL, n = 1), and rather unexpectedly in no MRD⁺ patient (n = 8).

OS was negatively affected by age >55 years and TP2 MRD, with only the latter retaining its poor prognostic impact in multivariate regression analysis (Figure 5). Regarding DFS, a high WBC count, Ph-like ALL feature, and TP2 MRD predicted a worse outcome in univariate analysis, with Ph-like ALL and TP2 MRD confirmed in regression analysis. On assessing prognostic interactions, the outlook of patients aged ≤55 years with a negative TP2 MRD and a non–Ph-like ALL was particularly favorable, especially for those aged 18 to 40 years, whereas TP2 MRD⁺ patients aged >55 years and/or diagnosed with a Ph-like ALL fared significantly worse (supplemental Figure 9).

Chemotherapy and HSCT toxicities in this study did not differ from prior risk-oriented regimens.^9,35 With blinatumomab 1 and blinatumomab 2, a total of 41 and 22 AEs of any type and grade were recorded in 29 and 17 patients, respectively (supplemental Table 10). Most AEs were grade 2 (n = 17) and grade 3 (n = 27), with fewer grade 4 (n = 10), and were mainly neurotoxic AEs (n = 32; grade 2, n = 9; grade 3, n = 19; and grade 4, n = 3). Fever and cytokine release syndrome were of lesser concern. These toxic side effects led to blinatumomab infusion delays up to a maximum of 57 days (n = 14) and some dose reductions (<75% planned dose, n = 12; 75%-89% planned dose, n = 13). Altogether, 96 patients (78.6%) received ≥90% of the planned dose, and a permanent drug discontinuation became necessary in only 8 patients (6.5%), of 184 total blinatumomab courses.

In this phase 2 GIMEMA trial, 2 blinatumomab courses were added to early consolidation of a standard program for adult Ph^– B-ALL, focusing on the optimization of MRD response and related clinical effects. Of note, remission patients were assigned to a final maintenance chemotherapy or allo-HSCT based on the risk subset and pre-blinatumomab MRD.

The study rationale combined different elements. First, in R/R ALL, blinatumomab was more effective at the first salvage attempt than subsequent ones,^15-17,21,22 prompting evaluation in the least advanced phase, that is untreated disease.²³ Further evidence came from the successful MRD⁺ ALL studies including many CR1 patients,^18-20 in whom MRD positivity was associated with a very high risk of relapse and death.^30-33 Most patients turned MRD⁻ after blinatumomab and experienced a survival benefit compared with historical data. Last, ∼25% of MRD⁻ patients are bound to relapse, presumably because of MRD levels below the sensitivity threshold of standard real-time quantitative polymerase chain reaction (RQ-PCR).^38,39 Although newer methods may detect lower-level MRD,^40,41 none of these assays was available for our study that involved rapid MRD assessment for therapeutic decisions, making blinatumomab an objectively appealing study drug even for patients labeled as MRD⁻. The scope of this last issue was recently addressed in the E1910 phase 3 study, which reported a markedly improved outcome for blinatumomab-treated MRD⁻ patients compared with the control arm.²⁶ 

With these premises, this combinatory program for Ph^– B-ALL was feasible without any documented exacerbation of the toxicities associated with pediatric-inspired chemotherapy, allo-HSCT, or blinatumomab immunotherapy.^{9,15,16,18,21} The study enrolled 149 patients aged between 18 and 65 years, 89% of whom achieved CR and proceeded to blinatumomab (92% of CR patients) before receiving the assigned risk-oriented treatment. The median OS, EFS, and DFS were not reached, and the projected 3-year OS was 71%. The results were remarkable in the chemotherapy assignment group (3-year OS, 91%; DFS, 75%) and somewhat less favorable in patients assigned to allo-HSCT (3-year OS 59%, DFS 50%) due to their higher risk of relapse and transplant-related mortality, although with a better outcome among transplant recipients (OS, 69%; DFS, 63%). The global risk of relapse and incidence of remission mortality was 28% and 7%, respectively. Although treatment outcome was significantly improved in younger patients, a survival rate in the 50% range was nonetheless observed in patients aged >55 years: CR of 93% in those aged 18 to 55 years vs 68% in >55 years (P = .002); 3-year OS, EFS, and DFS rates of 77%, 66%, and 70% in those aged 18 to 40 years vs 72%, 59%, and 61% in those aged 41 to 55 years vs 51%, 41%, and 51% in >55 years, respectively (OS, P = .0004; EFS, P = .0033; DFS, P = .46). The higher induction mortality in older patients is reducible using immunotherapy regimens with little or no associated chemotherapy.^24,28,42 

Of the 122 blinatumomab-treated patients, 109 had paired TP2/TP3 marrow MRD samples to fulfill the primary study objective. After blinatumomab 1, the MRD negativity rate increased from 72% to 93% (P < .0001), with 23 of 30 TP2 MRD⁺ patients (73%) reverting to MRD negativity. These results compare well with the study by Goekbuget et al,^18,20 in which blinatumomab monotherapy induced MRD negativity in 60 of 73 CR1 patients (82%) with MRD ≥10^–3, although we may argue that our study involving a shorter pre-enrollment phase of unselected patients could include more patients with VHR characteristics.

Although the survival probability for the entire blinatumomab treatment group was globally high and was not directly affected by post-blinatumomab MRD status, TP2 MRD⁺ patients experienced a less favorable outcome despite a high MRD⁻ conversion rate after blinatumomab and their eligibility to allo-HSCT (median and 3-year survival of 33.7 months and 43%, respectively). In the pivotal MRD⁺ ALL trial, the median survival was 29.5 months and ∼50% in HSCT recipients.^18,20 Altogether, these findings cast a higher-risk score on this patient subset than pre-blinatumomab MRD⁻ patients, for whom the projected survival at 78% in our study was more consistent with the E1910 trial results in MRD⁻ blinatumomab recipients.²⁶ A recent German study provided further evidence on how difficult or unpredictable the management of MRD can be, reporting a lower-than-expected 55% MRD⁻ conversion rate after blinatumomab in 40 MRD chemotherapy-resistant patients.⁴³ In our study, most TP2 MRD⁺/TP3 MRD⁻ patients expressed poor risk characteristics, such as a high WBC count, KMT2A rearrangements, a Ph-like ALL genotype, and other adverse genetic abnormalities, and the relapse rate was still relatively high after an allograft, although reduced compared with nonallograft patients, similar to the international MRD⁺ ALL trial.²⁰ Moreover, a French study reported a heterogeneous clinical course after blinatumomab in different genetic subsets of MRD⁺ HR B-ALL.⁴⁴ 

Based on the available data, chemotherapy MRD-resistant patients with associated HR characteristics should be considered for an allo-HSCT even if responsive to blinatumomab, using uniform protocolized conditioning and immunosuppressive regimens, with an intensive posttransplantation monitoring to detect and manage an early MRD recurrence. To gain more knowledge on this very challenging disease subset, we suggest the sharing of refined risk models to facilitate interstudy comparisons^45,46 and to implement a precision medicine approach correlating genetics/cytogenetics, MRD, and individual drug sensitivity patterns.⁴⁷ Concerning bispecific T-cell engagers, studies on the mechanisms of resistance^48-52 and restoration of defective T-cell immune functions⁵³ are warranted, together with the evaluation of the subcutaneous formulation of blinatumomab, highly active in R/R B-ALL.⁵⁴ 

This multicentric study proved the feasibility of an intensive chemotherapy and blinatumomab program for untreated Ph^– B-ALL in patients aged between 18 and 65 years. With an early MRD⁻ rate >90%, the 3-year survival was 71%, with even better results in patients aged ≤55 years, with early MRD negativity, or receiving the planned allo-HSCT according to the risk-oriented design. The main points of weakness were the total patient number (CR, n = 132), which did not allow for a precise assessment of treatment efficacy in smaller but significant risk subsets, the administration of only 2 blinatumomab courses in view of the positive results reported with ≥4 cycles in both Ph^– and Ph⁺ ALL,^25,26,55 and the heterogeneous management of Ph-like ALL, which was not always considered a transplant-eligible entity. The study demonstrated the usefulness of blinatumomab in early consolidation, in relation to MRD, risk stratification, and risk-oriented therapy. This and other blinatumomab-based studies are providing the evidence for the use of blinatumomab as a standard new agent for the frontline management of adult Ph– B-ALL.

This work was supported by the Associazione Italiana Ricerca sul Cancro, Special 5x1000 Program Metastases, Milan, Italy (21198 [R.F.]); and the Progetto di Ricerca di Rilevante Interesse Nazionale (prin 20222e c7la [S.C.]). The study drug (blinatumomab) and a research grant were kindly provided by Amgen Italy to the GIMEMA Foundation (agreement signed on 12 December 2017).

Contribution: R.B. designed and led the study, analyzed the data, and wrote the manuscript; R.F. was coprincipal investigator, designed and conducted the study, and edited the manuscript; S.C. and A.R. designed and conducted the study, analyzed the data, and edited the manuscript; A.R. designed and conducted the study and analyzed the data; S.C., M.D.T., and D.C. conducted correlative analysis (minimal residual disease [MRD] and Philadelphia chromosome–like acute lymphoblastic leukemia); I.D.S., A.S., O.S., M. Tosi, L.E., D.C., and M.S.D.P. performed research, conducted correlative analysis, and analyzed the data (MRD and cytogenetics/genetics); M.M., V.A., and A.P. performed statistical analysis and analyzed the data; M.P., F.L., M.A., P.C., P.Z., E.B., M. Leoncin, C.C., M.B., F.D.R., F.G., M. Tiribelli, A.C., A.L., E.A., M. Lunghi, and A.M.M. conducted the study and analyzed the data; A.P. provided the statistical design and analyzed the data; P.F. managed the study; and all the authors revised and approved the manuscript.

Conflict-of-interest disclosure: R.B. served on the speakers bureau and advisory boards for Amgen, Incyte, and Servier. S.C. served on the speakers bureau for Amgen, Incyte, AbbVie, Gilead, and Pfizer. R.F. served on the speakers bureau for Amgen, Novartis, and Incyte. F.L. served on the speakers bureau for Amgen, Pfizer, Incyte, Bristol Myers Squibb (BMS), and AbbVie; and served on advisory boards for Pfizer, Incyte, BMS, AbbVie, and Clinigen. P.Z. served on the speakers bureau for Astellas, Menarini Stemline, AbbVie, Incyte, Pfizer, and BMS; and served on advisory boards for Pfizer and BMS. E.B. served on the advisory boards for Amgen, AbbVie, and Otsuka. M. Lunghi served on the advisory board for Amgen. M.B. received travel grant and honoraria from Incyte, Janssen, and AbbVie. A.C. reports honoraria (consultancy, speaker, and advisory role) and/or travel support from AbbVie, Astellas, Janssen, Jazz, Celgene, Gilead, Pfizer, Incyte, and Amgen. M. Tiribelli served on the speakers bureau for BMS, Novartis, and AbbVie; and served on advisory boards for BMS, Novartis, and GlaxoSmithKline. A.L. served on the speakers bureau for AbbVie. A.R. served on the advisory boards for Amgen, Novartis, Kite-Gilead, Jazz, Omeros, Sanofi, and Italfarmaco. The remaining authors declare no competing financial interests.

Correspondence: Renato Bassan, UOC Ematologia, Ospedale dell’Angelo, Via Paccagnella 11, 30171 Venice, Italy; email: bassanre@gmail.com.