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Among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, treatment with the bispecific anti-CD19 and anti-CD3 monoclonal antibody blinatumomab resulted in longer overall survival and higher remission rates than did chemotherapy. The prognosis for adults with newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past three decades. With the use of intensive chemotherapy regimens, complete remission rates are 85 to 90% and long-term survival rates are 30 to 50%. 1 – 4 Still, most adults with B-cell precursor ALL will have a relapse and will die from complications of resistant disease or associated treatment. Among adults with relapsed or refractory ALL, remission rates are 18 to 44% with the use of standard salvage chemotherapy, but the duration of remission is typically short. 5 – 10 A major goal in this population is to . . .

The addition of blinatumomab to consolidation chemotherapy in adults with B-cell precursor acute lymphoblastic leukemia who had minimal residual disease–negative status after treatment improved overall and relapse-free survival.

B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes. We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or higher risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival. The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a higher relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone. Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).

The addition of rituximab to every phase of treatment (induction, consolidation, and maintenance) in adults with acute lymphoblastic leukemia improves outcomes, as compared with chemotherapy alone. The outcome for adults with acute lymphoblastic leukemia (ALL) has significantly improved over the past decade, notably because of treatment with more intensive chemotherapy, similar to that used for pediatric ALL, and risk-adapted use of allogeneic hematopoietic stem-cell transplantation. 1 , 2 Biologic features of some ALL subtypes have also offered opportunities for targeted treatments. Although tyrosine kinase inhibitors are now used to treat Philadelphia chromosome (Ph)–positive ALL, one of the most promising new approaches relies on the use of monoclonal antibodies targeting the CD19, CD20, CD22, CD33, and CD52 surface antigens expressed by ALL blast cells. 3 , 4 The use of rituximab, . . .

Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1–18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P  >  0.999), anti-pegaspargase antibodies (P  =  0.327), or pancreatitis (P  =  0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P  <  0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.

The added value of IKZF1 gene deletion ( IKZF1 del ) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1 del in a large cohort of children ( n =1223) with BCR - ABL1 -negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1 del had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75–3.32; P <0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1 del remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1 del increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19–5.55; P= 0.013) and in ‘B-other‘ ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45–3.39; P< 0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1 del -positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3–99.0 versus 42.1; 95% CI=20.4–62.5). Thus, IKZF1 del retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in ‘B-other‘ ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1 del patients in preventing relapses.

Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P =0.03). In cox multivariate regression analysis, sex (male worse; P =0.06), age (higher age worse, P =0.02), and TPMT activity (wild type worse; P =0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival ( P =0.82), possibly because of an excess of secondary cancers among these 75 patients ( P =0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.

Adolescent and young adult (AYA) patients 16–30 years old with high-risk acute lymphoblastic leukemia (HR-ALL) have inferior outcomes compared to younger HR-ALL patients. AALL0232 was a Phase 3 randomized Children’s Oncology Group trial for newly diagnosed HR B-ALL (1–30 years). Between 2004 and 2011, 3154 patients enrolled with 3040 eligible and evaluable for induction. AYA patients comprised 20% of patients (16–21 years, n = 551; 22–30 years, n = 46). 5-year event-free survival and overall survival was 65.4 ± 2.2% and 77.4 ± 2.0% for AYA patients compared to 78.1 ± 0.9% and 87.3 ± 0.7% for younger patients (p < 0.0001). Five-year cumulative incidence of relapse was 18.5 ± 1.7% for AYA patients and 13.5 ± 0.7% for younger patients (p = 0.006), largely due to increased marrow relapses (14.0 ± 1.5% versus 9.1 ± 0.6%; p < 0.0001). Additionally, induction failure rate was higher in AYA (7.2 ± 1.1% versus 3.5 ± 0.4%; p < 0.001) and post-induction remission deaths were significantly higher in AYA (5.7 ± 1.0% versus 2.4 ± 0.3%; p < 0.0001). AALL0232 enrolled the largest number of AYA B-ALL patients to date, demonstrating significantly inferior survival and greater rates of treatment-related toxicities compared to younger patients. Although treatment intensification has improved outcomes in younger patients, they have not been associated with the same degree of improvement for older patients.

Background Blinatumomab is a BiTE® immuno‐oncology therapy indicated for the treatment of patients with relapsed or refractory (r/r) B‐cell precursor (BCP) acute lymphoblastic leukemia (ALL). Aims To assess the efficacy and safety of blinatumomab as first salvage versus second or later salvage in patients with r/r BCP ALL. Materials & Methods Patient‐level pooled data were used for this analysis. In total, 532 adults with r/r BCP ALL treated with blinatumomab were included (first salvage, n = 165; second or later salvage, n = 367). Results Compared with patients who received blinatumomab as second or later salvage, those who received blinatumomab as first salvage had a longer median overall survival (OS; 10.4 vs. 5.7 months; HR, 1.58; 95% CI, 1.26–1.97; P < .001) and relapse‐free survival (10.1 vs. 7.3 months; HR, 1.38; 95% CI, 0.98–1.93; P = .061), and higher rates of remission (n = 89 [54%] vs. n = 150 [41%]; odds ratio, 0.59; 95% CI, 0.41–0.85; P = .005), minimal residual disease response (n = 68 [41%] vs. n = 118 [32%]), and allogeneic hematopoietic stem cell transplant (alloHSCT) realization (n = 60 [36%] vs. n = 88 [24%]), and alloHSCT in continuous remission (n = 33 [20%] vs. n = 52 (14%]). In a subgroup analysis, there was no apparent effect of prior alloHSCT on median OS in either salvage group. The safety profile of blinatumomab was generally similar between the groups; however, cytokine release syndrome, febrile neutropenia, and infection were more frequent with second or later salvage than with first salvage. Discussion In this pooled analysis, the logistic regression analyses indicated greater benefit with blinatumomab as first salvage than as second or later salvage, as evident by the longer median OS, longer median RFS, and higher rates of remission. Conclusion Overall, blinatumomab was beneficial as first salvage and as second or later salvage, but the effects were favorable as first salvage. This pooled analysis of three clinical studies assessed the efficacy and safety of blinatumomab as first salvage versus second or later salvage in patients with relapsed or refractory (r/r) B‐cell precursor (BCP) acute lymphoblastic leukemia (ALL). Compared with patients who received blinatumomab as second or later salvage, those who received blinatumomab as first salvage had a longer median overall survival, relapse‐free survival, and higher rates of remission, minimal residual disease response, and allogeneic hematopoietic stem cell transplant (alloHSCT) realization. Overall, blinatumomab was beneficial as first salvage and as second or later salvage, but the effects were favorable as first salvage.

The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities. The ICC classification incorporates recent clinical, cytogenetic, and molecular data, with a particular emphasis on whole transcriptome analysis and gene expression (GEX) clustering studies. B-ALL classification is modified to further subclassify BCR::ABL1-positive B-ALL and hypodiploid B-ALL. Additionally, nine new categories of B-ALL are defined, including seven that contain distinguishing gene rearrangements, as well as two new categories that are characterized by a specific single gene mutation. Four provisional entities are also included in the updated B-ALL classification, although definitive identification of these subtypes requires GEX studies. T-ALL classification is also updated to incorporate BCL11B-activating rearrangements into early T-precursor (ETP) ALL taxonomy. Additionally, eight new provisional entities are added to the T-ALL subclassification. The clinical implications of the new entities are discussed, as are practical approaches to the use of different technologies in diagnosis. The enhanced specificity of the new classification will allow for improved risk stratification and optimized treatment plans for patients with ALL.