Adult Acute Lymphoblastic Leukemia: 2025 Update on Diagnosis, Therapy, and Monitoring

Abstract

Disease Overview:

Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells arising in the bone marrow and extramedullary sites. While it is the most common pediatric cancer, ALL is a rare disease overall, with approximately 6,800 new cases diagnosed in 2024. Current treatment relies on multiagent chemotherapy administered over 2–3 years, resulting in long-term survival in 80–90% in pediatric patients compared to 40%–50% in adult patients, depending upon patient- and disease-specific characteristics.

Philadelphia chromosome-positive B-cell ALL:

Historically considered a poor risk ALL subtype, the treatment and outcome of Philadelphia chromosome (Ph)-positive B-cell ALL were drastically changed with the advent of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). The combination of a TKI with a backbone of multiagent chemotherapy, or more recently blinatumomab, is the mainstay of therapy, resulting in 5-year survival rates of 80+%. Achieving a complete molecular remission, particularly by next generation sequencing, is an important prognostic indicator which may identify patients who may avoid allogeneic stem cell transplantation (SCT).

Philadelphia chromosome-negative B-cell ALL:

The treatment approach for patients with Ph-negative B-cell ALL was historically composed of a chemotherapy backbone (either pediatric-inspired, or Hyper-CVAD based). Novel agents including inotuzumab ozogamicin and blinatumomab are being incorporated into these regimens to improve the rates of measurable residual disease-negativity and long-term outcomes. While differences in long-term survival rates differ between age groups such as adolescent and young adults compared to older adults (>60 years), with these immunotherapy-chemotherapy regimens, the 4-year survival rates have improved to 80–85% among patients who are able to receive these treatments. Elderly patients represent a difficult population to treat due to poor chemotherapy tolerance, high-risk disease features, and increased risk of developing therapy-related myeloid neoplasms. Use of inotuzumab ozogamicin and blinatumomab in lieu of intensive chemotherapy in this population has improved safety and efficacy in patients ≥60 years. Clinical trials incorporating chimeric antigen receptor (CAR) T-cell therapy into treatment for older patients are in progress.

T-cell ALL:

Combination chemotherapy regimens incorporating pegylated asparaginase and nelarabine are the standard for patients with T-cell ALL. Early T-cell precursor (ETP) ALL is a high-risk subgroup for which allogeneic SCT should be considered. Inclusion of the BCL-2 inhibitor venetoclax into treatment for patients with ETP-ALL may be beneficial and is currently being investigated.

Salvage therapy:

Several therapies are approved as single agents in the salvage setting. However, the best outcomes are obtained with combination therapy including chemo- and immunotherapies followed by CAR T-cell consolidation and allogeneic SCT. Clinical trials optimizing this approach are ongoing.

1. Disease Overview

Acute lymphoblastic leukemia (ALL) is a hematologic disease characterized by clonal proliferation and accumulation of lymphoid progenitor cells in the bone marrow in addition to extramedullary sites.^1–3 According to the Surveillance, Epidemiology, and End Results database, there were approximately 6,800 new cases and 1,300 deaths from ALL in the United States (U.S.) in 2024.^4,5 ALL has a bimodal age distribution, with the first peak occurring around 5 years of age and the second around 50 years of age. Widely known as a pediatric leukemia, 50–60% of cases occur in children and approximately 60% of patients are diagnosed before the age of 20. ALL is relatively rare during adolescence and young adulthood; only 25% of patients are diagnosed between ages 20–60. Adults aged 60 years and above make up approximately 11% of new diagnoses.^1,4,6 Recently identified inherited genetic variants associated with ALL susceptibility differ by ethnicity, aligning with observed ethnic disparities in ALL incidence.^7–9

ALL in the pediatric population is hallmarked for its treatment success, with cure rates of ≥ 80%.^1,10 This has been achieved through optimizing the delivery of cytotoxic chemotherapy agents developed over the past 50 years.^1,11 Unfortunately, these strategies have fallen short in the treatment of adult patients, resulting in cure rates of only 40–50%.^3,12–17 The discordance in outcomes observed between pediatric and adult patients is multifactorial. Adults with ALL frequently present with comorbidities which contribute to poorer tolerance of intensive chemotherapy. In addition, adults more often present with high-risk disease features such as adverse genetic subtypes and greater enrichment for alterations in epigenetic modifiers, predisposing them to chemotherapy resistance, resulting in lower response rates and higher incidence of relapse.^7,18–20 On the other hand, childhood ALL is characterized by more “favorable” cytogenetic and molecular abnormalities [hyperdiploidy; ETV6::RUNX1 rearrangement /t(12;21)] and less aggressive features (lower incidence of BCR::ABL1-like phenotype). In addition, children with ALL have better tolerance and better drug metabolism, therefore achieve a higher overall dose-intensity compared with adults.^8,21 These differences call for the need to design innovative curative therapeutic pathways in the adult population.

A greater understanding of the underlying disease pathogenesis leading to development of novel therapies, in addition to improvement in disease prognostication and utilization of risk-adapted treatment, have led to progress in overall outcomes over the past decade. ^14,22–26

Targeted agents including the BCR::ABL1 tyrosine kinase inhibitors (TKIs) as well as antibodies targeting specific cell surface antigens CD19, CD20, and CD22 represent breakthroughs in the treatment of ALL. ^{22,23,27–32} Contemporary treatment regimens now result in long-term survival rates of approximately 80–90% in Philadelphia chromosome-positive (Ph-positive) ALL,^24,30,33,34 80% in Burkitt’s disease and precursor B-cell ALL,^{14,32,35–38} and 70% in T-cell ALL among patients who are able to receive treatment with these new approaches.^39,40 Allogeneic stem cell transplantation (SCT) in first remission remains the curative approach for high-risk ALL.⁴¹

2. Clinical Presentation

Patients with ALL can present with various nonspecific signs and symptoms. For example, patients may present with constitutional symptoms (fever, night sweats, unexplained weight loss), infections, easy bleeding/bruising, dyspnea, and/or fatigue.^42,43 Upon physical examination, patients may exhibit petechiae, pallor, or ecchymoses due to low blood counts. Pediatric patients may present with pain in their extremities and joints due to leukemic infiltration of the synovium or synovial fluid, in addition to regression in development milestones (e.g. walking) in young children.⁴⁴ Unlike acute myeloid leukemia, leukostasis, characterized by abnormal intravascular leukocyte aggregation and clumping, is rare in ALL, even in the setting of severe leukocytosis. This may be due to the relatively smaller size and lower viscosity of lymphoblasts compared with myeloblasts.

The presence of extramedullary disease is common. Splenomegaly and/or hepatomegaly are observed in approximately 20% of patients at diagnosis due to organ leukemic infiltration. Other sanctuary sites include the testis and central nervous system (CNS). The mediastinum is a common extramedullary site in patients with T-cell ALL.^44,45 Notably, patients with mature B-cell ALL (Burkitt’s disease), may present with massive adenopathy, particularly in the abdomen, and are at high risk of tumor lysis syndrome and acute kidney injury, even prior to the initiation of treatment.^35,46 Among those with initial CNS involvement, 5–8% present with cranial neuropathies and meningeal infiltration.^45,47,48 Approximately 40–50% of patients with Burkitt-like ALL may complain of numbness of the chin, the lower lip and the buccal and gingival mucosa. This is a sensory neuropathy resulting from marrow expansion in the mandible and impingement on (or direct involvement of) the inferior alveolar branch of the trigeminal nerve.⁴⁹

3. Diagnostic Evaluation

The diagnosis of ALL requires ≥ 20% bone marrow lymphoblasts.^50–52 Further critical assessments include multiparameter flow cytometric (MFC) immunophenotyping to properly identify B-lineage or T-lineage disease (Supplemental Table 1). B-cell ALL is more frequent, comprising 75%–80% of adult cases. Cytogenetic and molecular analyses should also be conducted to detect for the presence of the Philadelphia chromosome [Ph, t(9;22)] and/or other cytogenetic abnormalities, for proper risk stratification.

3.1. Morphology and Immunophenotyping

The 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors (WHO-HAEM5) recognizes B-cell ALL as a precursor B lineage neoplasm comprised of lymphoblasts that express CD19, CD22, CD79a, and/or PAX5, as well as markers of immaturity including TdT and CD34, and lacking surface immunoglobulin expression.⁵¹ The classification of B-cell ALL in WHO-HAEM5 prioritizes the recognition of defining genetic alterations summarized in Table 1. When common genetic alterations cannot be detected, the diagnosis would revert to B-cell ALL, not otherwise specified (NOS). The most common B-cell ALL types include those with hyperdiploidy, hypodiploidy, and known genetic drivers such as iAMP21, BCR::ABL1, KMT2A rearrangements, or specific fusion genes. New entities added to WHO-HAEM5 include B-cell ALL with TCF3::HLF, which is separated from the similar TCF3::PBX1 fusion, due to its aggressive clinical course, and B-cell ALL with ETV6::RUNX1-like features, which shares characteristics with B-cell ALL with ETV6::RUNX1.⁵¹ In addition, WHO-HAEM5 allows for classification of B-cell ALL with other defined genetic alterations representing provisional biologic B-cell ALL types. The International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias distinguish 23 subtypes of B-cell ALL in contrast to the 13 subtypes defined by the WHO. The notable differences include separating BCR::ABL1-like into three distinct entities including ABL1-class rearranged, JAK-STAT activated, and BCR::ABL1-like, NOS. In addition, the ICC delineates BCR::ABL1-positive ALL into two entities based on the detection of BCR::ABL1 by FISH in granulocytes, representing multilineage involvement, or only in lymphoblasts, as in lymphoid only involvement in an effort to distinguish between the subset more closely related to CML-LBP (CML in lymphoid blast phase) versus BCR::ABL1-positive ALL. Additional subtypes in the ICC include B-cell ALL with MYC rearrangement (included only in B-cell lymphomas in the WHO), DUX rearrangement, MEF2D rearrangement, ZNF384(362) rearrangement, NUTM1 rearrangement, HLF rearrangement (in contrast to TCF3::HLF fusion in the WHO), UBTF::AXN7L3/PAN3/CDX2 “CDX2/UBTF”, IKZF1 N159Y, and mutated PAX5 P80R, in addition to a number of provisional entities.⁵³

Table 1.

Genetic alterations in ALL

Alteration	Incidence	Prognosis
BCR::ABL1-like 7,8,69,161,163	25–35%	↓ Survival (in particular if CRLF2 overexpressed, JAK mutation)
IKZF19,65,66,103,212	30–50% (Ph−) 60–80% (Ph+)	↓ Survival in most studies (focal deletions) (esp. with PAX5 or CDKN2A/B mutations in Ph+)
PAX5105	~40%	No effect on survival (Ph−) ↓ Survival (Ph+)
CDKN2A/B105	~40%	↓ Survival
EBF17,8	10–20% (Ph−) <10% (Ph+)	↓ Survival (Ph−)
RB17,8	10–20% (Ph−)	↓ Survival
TP5358,59,62	20–35% (Ph−) <5% (Ph+)	↓ Survival
JAK/STAT pathway7,8,18,68 (JAK1/2, IL7R, CRLF2)	10–20% (Ph−)	↓ Survival
RAS/RTK pathway7,8,18,68 (FLT3, KRAS, NRAS)	20–30% (Ph−)	↓ Survival
KMT2A-rearranged31,168	~75–80% (infants) ~10% (Adults)	↓ Survival

WHO-HAEM5 recognizes T-cell ALL as a precursor T lineage neoplasm comprised of lymphoblasts that express surface and/or cytoplasmic CD3, CD5, CD7, and other T lineage-associated markers such as CD2, CD4 and/or CD8. TdT and CD34 are also typically expressed.⁵¹ The classification recognizes T-cell ALL, NOS and ETP-ALL. The latter is defined based on expression by blasts of a specific immunophenotype that includes absent CD1a expression, absent CD8 expression, absent or dim (<75%) CD5 expression, and positivity for 1 or more myeloid (CD11b, CD13, CD33, CD65, CD117) and/or stem cell (CD34, HLA-DR) markers. ETP-ALL is a high-risk category characterized by both high rates of induction failure and relapse (10-year relapse rate: 72% with ETP-ALL versus 10% with typical T-ALL).^54–56 This is in part due to the high level of genomic instability observed with this subtype in both the number and size of gene lesions.⁵⁷ The ICC separates ETP-ALL into ETP-ALL, NOS and ETP-ALL with BCL11B rearrangement.⁵³ While not a distinct entity, “near-ETP ALL” has a similar immunophenotype as ETP-ALL except with higher CD5 expression (>75% of cells). Outcomes among patients with near-ETP ALL are more similar to those with non-ETP ALL than those with ETP-ALL therefore is not considered a high-risk subtype.⁵⁵

3.2. Cytogenetic and Genomic Classification

Cytogenetic and genomic analyses provide key prognostic information for patients with both B-cell ALL and T-cell ALL. Detection of the Philadelphia chromosome [Ph, t(9;22)] has evolved from a prognostic indicator to one that directly impacts therapy selection incorporating a BCR::ABL1 TKI into the treatment backbone. Burkitt leukemia [t(8;14), t(8;2); t(8;22)], hallmarked for its chemotherapy sensitivity and high risk of CNS involvement, also has therapeutic implications. While initial treatment selection may not be impacted, a full cytogenetic analysis is necessary for proper prognostication and to determine whether allogeneic SCT in first remission should be pursued. Poor risk cytogenetic abnormalities include hypodiploidy (<44 chromosomes) and complex karyotype (5 or more chromosomal abnormalities) as well as specific abnormalities including rearrangements in IgH, HLF, MEF2D, ZNF384, and KMT2A [t(4;11) or others], among others (Table 1). ^58,59 Hypodiploid B-cell ALL results in activation of RAS signaling and phosphoinositide 3-kinase (PI3K) pathways, potentially resulting in sensitivity to PI3K inhibitors. Further delineation of hypodiploid B-cell ALL into near-haploid (24–31 chromosomes) and low-hypodiploid (32–39 chromosomes) has been described based upon differences in downstream signaling.⁶⁰ Alterations in tyrosine kinase and RAS signaling (71%) as well as in the gene IKZF3 (13%) is observed in near-haploid ALL, whereas mutations in TP53 (91%), IKZF2 (53%), and RB1 (41%) characterize low-hypodiploid ALL.^58,59 ZNF384-rearranged ALL has a distinct immunophenotype expressing CD13 and/or CD33 with clinical features that depend on the fusion partner.⁶¹

In addition to cytogenetic aberrations, mutations in TP53 and IKZF1, as well as gene fusions and mutations comprising Philadelphia chromosome-BCR::ABL1-like ALL are considered high-risk features. Although TP53 mutations are typically observed among patients with low hypodiploidy, the presence of TP53 mutation signals a poor prognosis on its own. A retrospective analysis of 107 adult patients with TP53-mutated ALL demonstrated poor survival outcomes regardless of the presence of low hypodiploidy (median OS: 17 versus 19 months, p=0.89).⁶² Allelic frequency (AF) was shown to be prognostic in this cohort where the median overall survival (OS) among patients with TP53 AF >0.5 was 13 months compared to 25 months in those with TP53 AF <0.5 (p=0.03).⁶² This is in contrast to a previous retrospective analysis which reported similar survival among patients with or without TP53 mutation.⁶³ Numerically worse survival was observed among 13 patients with TP53 gene deletion (28 months versus not reached; p=0.2).⁶³ TP53-mutated ALL has also been shown to independently increase the risk of developing therapy-related myeloid neoplasms in adult patients after ALL therapy (9% versus 1%, p=0.008), particularly in elderly patients (age 60+ years and TP53 mutation carries a 25% risk of developing later acute myeloid leukemia or myelodysplastic syndrome compared to those with TP53 wild-type ALL).⁶⁴ BCR::ABL1-like ALL is an entity that is characterized by increased expression of hematopoietic stem-cell genes and reduced expression of B-cell lineage genes.⁶⁵ Despite being Ph-negative, patients with BCR::ABL1-like ALL have a similar gene expression profile as those with Ph-positive disease, including mutation of the IKZF1 gene, and tyrosine kinase pathway activation.^66,67 Common gene fusions and mutations observed in patients with BCR::ABL1-like ALL include CRLF2 rearrangement or overexpression (>50% of patients), JAK mutations, and ABL1, ABL2, CSF1R, and PDGFRB fusions, among others.^68–70 Sensitivity to commercially available kinase inhibitors such as BCR::ABL1 TKIs (in cases of ABL-class fusions; 10–20% of Ph-like ALL) and JAK inhibitors has been demonstrated.^68,71,72 Incorporating effective targeted agents (small molecule inhibitors, antibodies targeting CD19 and CD22) into the treatment for BCR::ABL1-like ALL may improve outcomes.⁶⁵

ETP-ALL is a unique entity in T-ALL that frequently harbors at least one genetic lesion in DNMT3A, FLT3, IDH1, IDH2, ETV6, with a low frequency of NOTCH1 mutations, in addition to activating mutations in genes regulating cytokine receptor and RAS signaling (67%).^73,74 It is also characterized by inactivating lesions disrupting hematopoietic development (58%) and histone-modifying genes (48%). The mutational spectrum is similar to what is observed in myeloid malignancies with a transcriptional profile similar to that of normal and myeloid leukemia hematopoietic stem cells.⁷³

In summary, genomic profiling in ALL has led to identification of new prognostic markers (e.g. IKZF1, TP53), therapeutic targets (e.g. ABL1), and novel ALL subtypes. Incorporating targeted therapies into the treatment paradigm of ALL therapy can hopefully improve the adverse prognosis of certain disease sub-types (e.g. BCR::ABL1-like ALL, ETP-ALL). Patients with high-risk features including low hypodiploidy (regardless of TP53 mutation), complex karyotype (≥5 chromosomal aberrations), KMT2A-rearranged, BCR::ABL1-like ALL with CRLF2 alteration and JAK1/2 mutation, persistent MRD-positivity after blinatumomab by NGS, or ETP-ALL should be considered for allogeneic SCT in fist CR.

4. Philadelphia Chromosome-Positive ALL

Success in the treatment of Ph-positive ALL relies on the combination of a BCR::ABL1 TKI targeting BCR::ABL1 with a backbone of cytotoxic chemotherapy of various intensity or blinatumomab. The multiagent regimen Hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine) has served as the traditional backbone for the treatment of this disease. Blinatumomab has recently demonstrated positive results in combination with dasatinib and ponatinib, possibly replacing the multi-agent cytotoxic chemotherapy backbone. Regardless of the backbone used, emphasis should be placed on continuous TKI use.^{24,27,29,30,75,76} Upon recognition of Ph-positive disease, a TKI should be immediately started and be administered continuously, rather than intermittently.²⁴ Managing TKI-specific toxicities is necessary for optimal administration and should be considered when choosing a TKI.

4.1. Imatinib-Based Regimens

The addition of imatinib to Hyper-CVAD was initially evaluated among 54 patients with either newly diagnosed or relapsed or refractory (R/R) Ph-positive ALL.⁷⁷ The combination resulted in a complete response (CR) rate of 93% and 5-year OS rate of 43% in the frontline setting. Sixteen patients (30%) underwent allogeneic SCT.⁷⁷ These results demonstrated significant improvement in long-term outcomes compared to what had been observed historically with chemotherapy alone.¹⁴

The UKALLXII/ECOG2993 trial evaluated the addition of imatinib to intensive chemotherapy administered during induction or in a sequential fashion. Improvements in CR rate (92% versus 82%; p=0.004), 4-year OS rate (38% versus 22%; p=0.003), and in the number of patients able to proceed to allogeneic SCT (71% versus 50%) was achieved with the addition of imatinib. Comparing the outcomes of patients treated with imatinib during induction therapy or later suggested that the earlier addition was more beneficial.⁷⁸ The phase 2 GMALL trial evaluated the use of imatinib alone for 6 weeks prior to the addition of low-intensity chemotherapy for a second induction phase, followed by consolidation with chemotherapy and then allogeneic SCT.⁷⁹ Among 174 adults with a median age of 42 years (range, 18–55 years), 85% achieved CR with imatinib alone and 42% achieved complete molecular response (CMR, BCR::ABL1 (IS) ≤0.01% for the p210 oncoprotein and ≥4-log reduction of BCR::ABL1 transcript levels for the p190 oncoprotein) after consolidation therapy. Most patients (98%) proceeded to allogeneic SCT in CR1 after a median of 4 months of treatment. At a median follow up of 52 months, the 3-year OS rate was 76% and remission duration rate at 3 years was 89% among those who achieved a response. Overall survival rate after three years post-SCT was 81%. Treatment-related mortality was 16% and was not different based upon whether patients were younger or older than 45 years.⁷⁹

In a randomized trial, imatinib was given during induction on Days 1–14 with low-intensity chemotherapy (vincristine plus dexamethasone) or high-intensity chemotherapy (Hyper-CVAD) in 268 adults with a median age of 47 years (range, 18–59 years).⁸⁰ The rates of major molecular response (MMR, ≥3-log reduction of BCR::ABL1 transcript levels), OS and event-free survival (EFS) were similar between the 2 groups, with a higher rate of early deaths in the high-intensity arm (6.7% versus 0.7%; p=0.01).⁸⁰ Allogeneic SCT was associated with a significant benefit in relapse-free survival (RFS) (HR, 0.69; p=0.036) and OS (HR, 0.64; p=0.02). However, there was no difference in outcomes after either autologous or allogeneic SCT in patients achieving MMR. Consistent with this observation, long-term follow-up results from MD Anderson showed that OS was similar among patients with or without allogeneic SCT, in particular in patients with eradication of residual molecular disease.⁷⁷ This suggests that allogeneic SCT may not be indicated in all patients with Ph-positive ALL, as discussed more thoroughly below.

4.2. Second Generation TKI-Based Regimens

Dasatinib and nilotinib, second-generation BCR::ABL1 TKIs, are more potent and selective than imatinib, and have each been studied in combination with a chemotherapy backbone, although there are no head-to-head studies evaluating these agents.

As with imatinib, dasatinib has been evaluated in combination with the Hyper-CVAD regimen, resulting in a CR rate of 96% and 5-year OS rate of 46% in 72 adults with newly diagnosed Ph-positive ALL.⁸¹ The complete cytogenetic response (CCyR) rate was 83% and CMR rate was 65%.⁸¹ Twelve patients (16%) proceeded to allogeneic SCT.⁸¹ Subsequently, a multicenter SWOG study demonstrated a similar CR rate of 88% and 3-year OS of 69% among 94 patients treated with Hyper-CVAD and dasatinib.⁷⁵ Notably, 41 patients (44%) underwent allogeneic SCT regardless of molecular response status and experienced significantly improved RFS (p=0.038) and OS (p=0.037) compared to those who did not proceed to allogeneic SCT.⁷⁵ Nilotinib, on the other hand, has been studied in combination with a schedule of alternating reduced-intensity and conventional chemotherapy (high-dose methotrexate, +/− high-dose cytarabine) followed by SCT and imatinib maintenance.⁸² Despite being stopped early due to higher relapses observed in the arm omitting high-dose cytarabine, an overall CMR rate of 83% and 4-year OS rate of 79% were observed among those receiving conventional chemotherapy with high-dose cytarabine.⁸² Early mortality was low (<5%) supporting the safety of adding nilotinib to a chemotherapy backbone.⁸² Overall, the addition of either dasatinib or nilotinib to intensive chemotherapy has demonstrated comparable rates of CR (96%–100%), CMR (60%–83%) and long-term survival (approximately 45%).^75,81 With low-intensity therapies, similar long-term survival rates of 36% with dasatinib and 47% with nilotinib have been reported.^83,84 While similar efficacy and resistance patterns largely driven by the T315I mutation are observed with either dasatinib or nilotinib, their safety profile differs where dasatinib is associated with pleural effusions while nilotinib is associated with more vascular arterio-occlusive events and metabolic problems.⁸⁵

Given the increased incidence in Ph-positive ALL with increasing age, and the potency of second- and third-generation TKIs, combining TKIs with lower-intensity backbones to improve tolerability without impacting efficacy continues to be explored. The EWALL-PH-01 study included patients 55 years and older with newly diagnosed Ph-positive ALL.⁸³ Treatment consisted of a combination of dasatinib with vincristine and dexamethasone for induction, followed by low-dose consolidation and maintenance therapy. With this strategy, 96% of patients achieved CR and 24% achieved CMR. The 5-year OS rate was 36%. Among the 24 patients who underwent ABL1 kinase mutation testing at relapse, 18 (75%) had a T315I mutation.⁸³ Another low-intensity regimen studied by the GIMEMA group included induction consisting of dasatinib and steroids alone, resulting in a CMR rate of 18% and 5-year OS rate of 56%.⁸⁶ Improved outcomes were observed among patients who obtained a molecular response by day 85 and among those who did not have additional IKZF1 plus CDKN2A/B and/or PAX5 deletions.⁸⁶ The EWALL-PH02 investigated the use of nilotinib with a backbone of vincristine and dexamethasone, resulting in a CR rate of 94% and a 4-year OS rate of 47%, similar to what was observed with the EWALL-PH-01 study.⁸⁴ Findings from these studies suggest that some patients who achieve CMR may experience long-term survival without intensive chemotherapy, emphasizing the necessity of a potent and tolerable TKI.

Among imatinib and the second-generation TKIs, the only randomized trial that exists is a randomized trial comparing imatinib and dasatinib in 189 pediatric patients.²⁸ Patients 18 years and younger were randomized to receive chemotherapy with imatinib 300 mg/m²/day or dasatinib 80 mg/m²/day. The dose of dasatinib was chosen in order to enhance CNS penetration.²⁸ The 4-year EFS and OS rates were significantly better with dasatinib (71% and 88.4%, respectively), compared to imatinib (49%, p=0.005; and 69.2%, p=0.04). The cumulative risk of any relapse was significantly lower with dasatinib (19.8% versus 34.4% at 4 years; p=0.01) as well as the risk of isolated CNS relapse (2.7% versus 8.4% at 4 years; p=0.06).²⁸

Despite the progress of chemotherapy and TKI combinations followed by allogeneic SCT, the long-term survival in Ph-positive ALL remained modest with 5-year survival rates of 40% to 65%. This suboptimal outcome was driven by two factors: 1) a suboptimal CMR rate of only 20%–50% in combination with low or high-intensity chemotherapy, and 2) the emergence of the T315I ABL1 kinase domain mutation, which has been reported in up to 75% of patients with Ph-positive ALL relapsing after first- and second-generation TKIs.^75,77,81,87 Thus, using more potent third generation TKIs might improve outcomes further by inducing higher CMR rates and suppressing the emergence of T315I mutations.

4.3. Ponatinib-Based Regimens

Ponatinib is a third generation TKI with potent activity against Ph-positive leukemias with both wild-type and mutated ABL1 kinase domain, including the T315I mutation.⁸⁸

Ponatinib was combined with Hyper-CVAD for the frontline treatment of patients with Ph-positive ALL.^33,76 After two fatal ischemic myocardial events, a risk-adapted ponatinib dosing strategy was implemented. Patients continued to receive ponatinib 45 mg Days 1–14 during induction, but the consolidation dose of ponatinib was reduced from 45 mg to 30 mg. Once patients achieved CMR, ponatinib was further reduced to 15 mg daily. No additional vascular events were observed after implementing this dosing strategy. Among 86 patients (median age 46 years; range 39–61 years) treated with Hyper-CVAD and ponatinib, 100% of patients with active disease at enrollment (n=68) achieved CR and no early deaths were reported.⁷⁶ The overall CMR rate was 84% and 20 patients (23%) underwent allogeneic SCT in CR1. The estimated 6-year OS rate was 75%. A 6-month landmark analysis did not demonstrate a difference in 6-year OS rates between those who proceeded to allogeneic SCT and those who did not (70% versus 87%). These encouraging results suggest the possibility of a paradigm shift in the treatment of Ph-positive ALL where allogeneic SCT may not be needed when CMR is achieved⁷⁶. The PONALFIL trial included 30 patients (median age 50 years; range 19–59) with newly diagnosed Ph-positive ALL who were treated with ponatinib 30 mg daily plus an intensive chemotherapy backbone.⁸⁹ The CR rate after induction was 100% and the overall CMR rate was 71%. Twenty-six patients (87%) proceeded to allogeneic SCT. The 4-year EFS and OS rates were 66% and 92%.⁹⁰ This reflects a considerable improvement with this regimen compared to the 3-year OS rate of 53% previously reported with the use of imatinib. Ponatinib was investigated with lower-intensity therapy in the phase 2 GIMEMA 1811 trial among 44 patients (median age 66 years; range, 26–85). Ponatinib was combined with steroids, resulting in an overall CMR rate of 41%, and an estimated 2-year OS rate of 66%.⁹¹

A propensity score-matched analysis comparing the outcomes of Hyper-CVAD in combination with either ponatinib or dasatinib demonstrated a superior CMR rate at three months (84% versus 63%) and 3-year OS rate (83% versus 56%; p=0.03) with ponatinib.⁹² A meta-analysis including 26 clinical trials also demonstrated higher CMR rates (79% versus 34%) and 3-year OS rates (79% versus 50%) with ponatinib compared to imatinib or second-generation TKIs.⁹³

The results of a multicenter phase 3 randomized trial (PhALLCON) comparing ponatinib to imatinib in combination with low-intensity chemotherapy demonstrated a higher rate of measurable residual disease (MRD)-negativity at the end of induction (34% versus 17%; p=0.002) as well as a higher rate of deep molecular responses (DMR, 42% versus 21%) with ponatinib versus imatinib. Arterial occlusive events were infrequent and comparable between the two arms (ponatinib/imatinib, 2%/1%).³⁰

4.4. Blinatumomab in Combination with BCR::ABL1 TKIs

Blinatumomab, a bispecific T-cell engager (BiTE) targeting CD3 and CD19, has demonstrated single-agent activity in patients with both Ph-negative and Ph-positive ALL. Among 45 heavily pre-treated patients with Ph-positive ALL, 36% achieved a response, including CMR in 88% of responders with blinatumomab alone. The median OS in the entire cohort was 7.1 months.⁹⁴ A retrospective analysis of patients with relapsed Ph-positive ALL or CML-LBP treated with the combination of blinatumomab and a TKI demonstrated a CMR rate of 75% and 1-year OS rate of 73% with a tolerable safety profile.⁹⁵

These promising results prompted the development of blinatumomab plus TKI combinations for frontline therapy of Ph-positive ALL (Table 2). The D-ALBA trial evaluated the efficacy of blinatumomab in combination with dasatinib in 63 patients (median age 54 years; range 24–82) with newly diagnosed Ph-positive ALL. Patients received corticosteroids and dasatinib alone for 85 days followed by the addition of 2–5 cycles of blinatumomab to continuous dasatinib and a total of 12 doses of prophylactic intrathecal (IT) chemotherapy.²⁷ The rate of molecular response (either CMR or a positive, nonquantifiable response) increased from 29% after induction to 60% at the end of two blinatumomab cycles.²⁷ Twenty-four patients (38%) proceeded to allogeneic SCT in first CR. The 4-year disease-free survival (DFS) rate was 76% and 4-year OS rate was 81% at a median follow-up of 53 months.⁹⁶ Among nine patients who relapsed, four had isolated CNS relapse.

Table 2.

Outcomes with BCR::ABL1 TKIs with Blinatumomab in Frontline Ph-positive ALL

	Blinatumomab + Dasatinib		Blinatumomab + Ponatinib
Treatment Schema	Induction: dasatinib days 1–84 Consolidation: blinatumomab x 2–5 cycles + dasatinib IT: 12 doses (n=63)96	Induction: dasatinib days 1–84 Consolidation: blinatumomab x 3 cycles + dasatinib IT: 8 doses (n=24)213	Induction/consolidation: blinatumomab x 5 cycles + ponatinib IT: 12–15 doses (n=76)34	Induction: ponatinib days 1–70 Consolidation: blinatumomab x 2–5 cycles + ponatinib IT: 15 doses (n=137)98
Median age, (range) years	54 (24–82)	73 (65–87)	50 (18–83)	57 (20–87)
CR rate (%)	98	92	96	96
CMR rate (%)1	93	89	83 (94% by NGS)	74
Median follow up	53 months	4.3 years	29 months	6.4 months
Survival rate (%)	81 (4-year)	75 (3-year)	88 (3-year)	92 (18 months)
Allogeneic SCT—n. (%)	30 (48)	1 (4)	2 (3)	16 (12)
Relapse—n. (%)	9 (14)	8 (33)	10 (13)	4 (3)
CNS relapse—n. (%)	4 (6)	NA	5 (7%	1 (0.7)
T315I at relapse—n. (%)	6 (10)	3 (13)	NA	1 (0.7)

CR: complete remission; CMR: complete molecular response; SCT: stem cell transplantation; CNS: central nervous system; IT: intrathecal; NGS: next generation sequencing; NA: not reported;

¹Evaluated by PCR

Considering the single-agent clinical activities of both ponatinib and blinatumomab in Ph-positive ALL, The MD Anderson Cancer Center conducted a phase 2 trial to evaluate this combination in the frontline setting.²⁹ In contrast to the D-ALBA trial, blinatumomab was initiated simultaneously during induction in combination with ponatinib, and patients received 12–15 doses of IT chemotherapy. Among 53 patients enrolled with active disease, 93% achieved a CR or CR with incomplete count recovery (CRi).³⁴ After induction, 59% of patients achieved a CMR and 83% achieved CMR overall. Additionally, 96% achieved MRD-negativity by a next-generation sequencing (NGS) assay (sensitivity 1×10⁻⁶). After a median of 29 months, 10 patients relapsed, including five with CNS relapse. The 3-year EFS rate was 78% and the 3-year OS rate was 88%.³⁴ Two patients had persistently detectable BCR::ABL1 transcripts of 0.01–0.05% and therefore underwent allogeneic SCT in first remission.⁹⁷ The infrequent use of allogeneic SCT in this cohort highlights that this highly effective combination may mitigate the reliance on allogeneic SCT in the frontline setting, particularly among patients able to achieve and sustain a CMR. With longer follow-up, CNS relapses have been observed mainly in patients presenting with a WBC count ≥70 K/µL, possibly attributed to the omission of high-dose chemotherapy. CNS-directed strategies are being developed to reduce the risk of CNS relapse (discussed below).

Similarly, the GIMEMA group has initiated the phase 3 ALL2820 trial to evaluate the use of ponatinib with blinatumomab versus imatinib and chemotherapy.⁹⁸ Only results from the experimental arm (blinatumomab and ponatinib) have been reported. As in the prior D-ALBA protocol, induction consisted of a steroid pre-phase followed by single-agent TKI with ponatinib 30–45 mg once daily for 70 days followed by the addition of blinatumomab. Among 137 patients (median age 57 years; range, 20–87), 96% achieved CR. After induction, 46% achieved CMR which increased to 74% after the second blinatumomab course. Allogeneic SCT was pursued in 12% of patients. After a median follow up of 6.4 months (range, 0.1–32.3 months), the estimated 18-month OS rate was 91.6%; four patients (3%) have relapsed, including one with CNS relapse.⁹⁸ Another phase 3 randomized trial (NCT04530565) comparing Hyper-CVAD to blinatumomab, each with either dasatinib or ponatinib, is also ongoing and anticipated to complete accrual this year.

Incorporation of blinatumomab into the frontline treatment of Ph-positive ALL has led to improvement in outcomes while avoiding toxicity of traditional chemotherapy. The combination with ponatinib has demonstrated high rates of CMR and a tolerable safety profile, improving outcomes while avoiding the need for allogeneic SCT in most patients. Omission of high-dose chemotherapy in this population has led to an increase in CNS relapses, leading to an increase in IT chemotherapy for this population as well as reconsideration of CNS-penetrating chemotherapy in patients with WBC≥70 K/µL at presentation.

4.5. Novel drugs

Asciminib inhibits the ABL1 kinase activity through binding to an allosteric site, the ABL myristoyl pocket, unlike the remaining BCR::ABL1 TKIs which bind to the ATP-binding site of the BCR::ABL1 oncoprotein. It was investigated in combination with dasatinib at 140 mg daily and corticosteroids in 24 patients with newly diagnosed Ph-positive ALL (n=22) or CML-LBP (n=2).⁹⁹ The asciminib recommended phase 2 dose was 80 mg daily due to the dose limiting toxicities of amylase and lipase increase (without pancreatitis) observed at 160 mg daily. The 3-month MR4 rate was 26% and 2-year OS rate was 75%.

Olverembatinib is a novel third-generation pan BCR::ABL1 TKI with demonstrated efficacy in patients with Ph-positive ALL as well as CML. In a phase 2 trial, olverembatinib 40 mg every other day was combined with venetoclax, vincristine, and prednisone in 31 patients (median age 40 years; range, 20 to 66).¹⁰⁰ The complete hematologic response rate was 100% and the 3-month CMR rate was 61.3%. The combination was well tolerated, with most adverse events grade 1–2. A retrospective review of 153 patients with CML in myeloid blast phase (CML-MBP; n=68), CML-LBP (n=39) or R/R Ph-positive ALL (n=46) treated with olverembatinib alone (19%) or in combination with chemotherapy (81%) was recently reported.¹⁰¹ Twenty patients (13%) were newly diagnosed, while 63 patients (41%) had been previously treated with 2 or more TKIs and 37% had a T315I mutation. Complete hematologic response rate at 3 months was 79% in those with CML-LBP and 83% in patients with R/R ALL (p=0.007). Patients with CML-LBP had the longest EFS (median 24 months, p=0.013) and OS (not reached, p=0.021) compared to CML-MBP (median 3 months and 9 months, respectively) or R/R ALL (median 7 months and 15 months, respectively). Patients who proceeded to allogeneic SCT had a significantly longer 1-year EFS rate (72% versus 27%; p<0.001) and OS rate (84% versus 40%; p<0.001) compared to those who did not. Cardiovascular related adverse events (e.g. hypertension, heart failure, deep vein thrombosis, cerebral infarct) occurred in 23 patients (16%).¹⁰¹

Future studies combining blinatumomab with asciminib or olverembatinib are warranted. Furthermore, subcutaneous (SC) blinatumomab has shown promising early activity in patients with relapsed/refractory ALL.¹⁰² If the safety and efficacy of SC blinatumomab is maintained with longer follow-up, it can possibly replace intravenous blinatumomab in the treatment of patients with Ph-positive ALL.

4.6. Impact of Disease Biology on Outcome and Treatment Strategies

Recurring genetic abnormalities such as IKZF1 and CDKN2A/2B deletions identified in Ph-positive ALL are associated with poor prognosis.^103–106 In an update of the D-ALBA trial, patients with the IKZF1^plus genotype had worse DFS at 53 months compared to patients with IKZF1 deletion alone or without IKZF1 deletions.⁹⁶ This suggests that IKZF1^plus aberrations confer a worse prognosis in patients treated with blinatumomab plus dasatinib, as also noted in patients treated with dasatinib and steroids, highlighting the need for alternative strategies in these patients. The presence of IKZF1 plus CDKN2A/B and/or PAX5 deletions was the most important negative prognostic factor for OS (p=0.005) and DFS (p=0.0008).⁸⁶

Among 76 patients treated with concomitant blinatumomab with ponatinib, the presence of VPREB1 deletion was associated with an increased risk of relapse (52% versus 17%; p=0.048). On multivariable analysis, the only significant risk factor predictive of relapse was baseline WBC ≥ 70 K/µL, whereas the presence of IKZF1^plus aberrations was not [HR: 2.37 (95%CI: 0.59, 9.53); p=0.22].⁹⁷ The ongoing ALL2820 trial treating patients with ponatinib monotherapy followed by the combination of blinatumomab and ponatinib has not yet reported outcomes associated with the impact of IKZF1^plus, however the recommendation of allogeneic SCT was based upon the presence of IKZF1^plus at baseline.⁹⁸

When comparing the survival of patients with IKZF1^plus treated with Hyper-CVAD plus ponatinib to those treated with Hyper-CVAD plus dasatinib, the 5-year OS rate was numerically higher among those who received ponatinib (62% versus 44%). However, in the non-IKZF1^plus (non-IKZF1 deletion or IKZF1 deletion alone) group, the 5-year OS rates were dramatically improved with Hyper-CVAD plus ponatinib compared with Hyper-CVAD plus dasatinib (97% versus 41%).¹⁰⁶ An ongoing randomized trial (GIMEMA ALL2820) is evaluating the role of SCT in this setting.¹⁰⁷

4.7. Allogeneic Stem Cell Transplantation

Allogeneic SCT has historically been considered the gold standard for all patients with Ph-positive ALL. Treatment developments with novel TKIs in combination with blinatumomab have significantly improved the long-term outcomes with little reliance on allogeneic SCT, raising the question of whether allogeneic SCT can be safely deferred in a select group of patients with newly diagnosed Ph-positive ALL. Among patients who proceed to allogeneic SCT, maintenance with a low-dose TKI post-SCT should begin between 30–90 days post-SCT based on engraftment and continue for three years, assuming the patient remains in CMR. In contrast, patients who do not proceed to allogeneic SCT should continue TKI therapy indefinitely. In our practice, we may consider stopping therapy in patients who have maintained CMR by NGS and PCR for at least five years. Stopping TKI therapy has been shown to be feasible among patients with Ph-positive ALL, however this approach needs to be tested in the setting of a prospective clinical trial.¹⁰⁸

Chalandon and colleagues evaluated the role of autologous SCT in the treatment of newly diagnosed Ph-positive ALL. Neither an improvement in RFS nor OS was observed among patients with MMR who underwent allogeneic SCT, indicating autologous SCT followed by TKI maintenance may be a viable option in patients with MMR.⁸⁰ Similarly, the significance of achieving CMR within 3 months of treatment initiation has also been demonstrated. An analysis of patients with newly diagnosed Ph-positive ALL who achieved CMR by three months and did not proceed to allogeneic SCT demonstrated a 4-year OS rate of 66% and median OS of 127 months. Achieving CMR by three months was the only prognostic factor for OS by multivariate analysis (HR: 0.42; p=0.01).¹⁰⁹ In a subsequent analysis of 84 patients with Ph-positive ALL who received Hyper-CVAD plus a TKI in the frontline setting, a 5-year progression-free survival (PFS) rate of 68% and 5-year OS rate of 72% was demonstrated among those who achieved CMR by three months.¹¹⁰ Treatment with ponatinib was the only favorable and independent factor predictive for relapse (HR: 0.39; p=0.03) or OS (HR: 0.38; p=0.04) by multivariate analysis, whereas allogeneic SCT was not. A large retrospective multicenter study including 230 patients with Ph-positive ALL treated with TKI-based regimens (intensive and non-intensive) who achieved CMR within three months of diagnosis did not demonstrate an improvement in RFS (HR: 0.86; p=0.53) or OS (HR: 1.05; p=0.86) among patients who proceeded to allogeneic SCT (n=98) versus not (n=132).¹¹¹ A propensity score analysis was also performed to account for imbalances in baseline risk factors and TKI use between both groups. The results confirmed the findings from the multivariate analysis by showing similar 5-year OS (68% versus 61%; p=0.63) and RFS (63% versus 52%; p=0.42) between patients who did or did not proceed to allogeneic SCT.¹¹¹

In addition to CMR by three months, the presence of MRD may also be used to identify patients who may benefit from allogeneic SCT. Among adults with Ph-positive ALL, MRD-positivity (defined as IG/TR ≥0.01%) after cycle 2 of therapy was an independent factor associated with worse DFS.¹¹² Baseline WBC ≥30 K/µL was also prognostic for worse DFS. Patients with at least one of these features were considered “high-risk” and found to have lower DFS and OS than the remaining population. Allogeneic SCT significantly improved DFS (HR: 0.33; p <0.001) and OS (HR: 0.29; p=0.001) in patients with “high-risk” disease, but not in those considered standard risk.¹¹²

Overall, a chemotherapy-free approach with blinatumomab and ponatinib leads to excellent outcomes in patients who achieve CMR. Patients with high-risk features including IKZF1^plus, high WBC upon presentation (≥ 70 K/µL), and possibly VEPRB1, as well as those who do not achieve CMR, may benefit from the addition of systemic chemotherapy, allogeneic SCT, and possibly chimeric antigen receptor (CAR) T-cell therapy.

4.8. Central Nervous System Prophylaxis

Improvement in remission duration and OS with the incorporation of TKIs into chemotherapy backbones for the treatment of Ph-positive ALL resulted in an increase in observed late and isolated CNS relapses in up to 10% to 15% of patients.^76,81,113 Consequently, treatment schemas for patients with Ph-positive ALL needed to incorporate more prophylactic IT chemotherapy. The Hyper-CVAD protocol, for example, increased the number of prophylactic IT chemotherapy doses from 8 to 12 for patients with Ph-positive disease.^48,76,81 This amendment improved the 3- and 6-year CNS RFS rates (3-year:100% versus 89%, p=0.049; 6-year:100% versus 91%, p=0.040), and was significantly associated with a reduction in CNS relapses (HR: 0.12; p=0.04).¹¹⁴

Notably, the emphasis on chemotherapy-free regimens with the combination of blinatumomab and TKIs lacks CNS-directed intensive chemotherapy (high doses of methotrexate and cytarabine), relying solely in prophylactic IT chemotherapy to reach the CNS. As a result, the risk of CNS relapses may be greater with these regimens. CNS relapses were observed in four (6.3%) of 63 patients treated with blinatumomab plus dasatinib and in four (5.3%) of 76 patients treated with blinatumomab plus ponatinib.^96,97 An analysis from the phase 2 trial of blinatumomab and ponatinib suggested that a WBC count 70 ×10⁹/L or higher at presentation was the only factor predictive for relapse, which was largely extramedullary in nature.⁹⁷ Ongoing strategies currently employed for patients treated with blinatumomab and ponatinib include 1) increasing the number of IT chemotherapy doses from 12 to 15; 2) incorporating 1–2 cycles of high-dose methotrexate and cytarabine in consolidation; and 3) considering consolidation with CAR T-cell therapy or allogeneic SCT with or without cranio-spinal irradiation.^34,114,115 These approaches may be considered for patients deemed at high risk of CNS relapse treated with blinatumomab-TKI combinations.

5. Philadelphia-negative B-cell ALL

5.1. Adult ALL

The adolescent and young adult (AYA; age 15–39 years) population is a specific subset of patients with ALL who tend to be enriched with higher risk features than pediatric patients, including BCR::ABL1-like ALL, and have benefitted from treatment with a pediatric-inspired regimen.^116–119 The results from the CALGB10403 trial demonstrated a 3-year survival rate of 73% among AYA patients treated with a pediatric-inspired protocol, emphasizing asparaginase and corticosteroids.¹¹⁹ The Hyper-CVAD regimen relies on more myelosuppressive agents rather than asparaginase and has resulted in similar outcomes among patients <40 years of age.^14,48 Monoclonal antibodies targeting leukemia cell surface antigens have been added to the treatment backbones of patients with Ph-negative ALL since 2000 when the MD Anderson studies demonstrated that the addition of the anti-CD20 antibody rituximab improved survival in younger patients treated with Hyper-CVAD.¹⁷ Subsequently, the GRAALL-R 2005 phase 3 randomized trial demonstrated an improvement in the 2-year rates of EFS (65% versus 52%; p=0.038) and OS (71% versus 64%; p=0.095) with the addition of rituximab to standard chemotherapy in patients <60 years of age.¹²⁰ Combinations with novel CD20 targeted therapies like the bispecific anti-CD3/CD20 T-cell engagers are highly anticipated.¹²¹

The addition of rituximab set the stage for the safe and effective incorporation of antibodies into the backbone of therapy for patients with Ph-negative B-cell ALL (Table 3). Blinatumomab and inotuzumab ozogamicin, the anti-CD22 antibody drug conjugate (ADC), each demonstrated significant survival benefits as single agents in the relapsed/refractory setting,^22,23 and since have been investigated in the frontline setting in combination with various chemotherapy backbones. Four cycles of blinatumomab have been added sequentially after 4 cycles of the Hyper-CVAD regimen in a phase 2 study in patients 14 years and older with newly diagnosed Ph-negative B-cell ALL.¹²² Blinatumomab courses could begin after only 2 cycles of chemotherapy in patients with persistent MRD-positivity, or otherwise considered high-risk based on baseline cytogenetics and molecular features. All 38 patients enrolled achieved CR and 97% achieved MRD-negativity by MFC. Thirteen patients (34%) proceeded to allogeneic SCT. The estimated 3-year RFS rate was 74% for the entire cohort (83% among patients aged 18–29 years). The estimated 3-year OS rate was 81%.¹²² The study was then amended to add inotuzumab 0.3 mg/m² on days 1 and 8 during two methotrexate-cytarabine cycles, and two blinatumomab cycles (cumulative dose 2.4 mg/m²). With the addition of the inotuzumab to the methotrexate-cytarabine cycles, the dose of methotrexate was reduced to 500 mg/m² and cytarabine to 1000 mg/m².¹²³ All 37 patients treated with this new schema achieved a CR, including 79% who achieved MRD-negativity by NGS.^123,124 With a median follow-up of 26 months (range, 8–39) in the Hyper-CVAD plus blinatumomab and inotuzumab cohort, there have been 3 relapses (all had WBC > 100 K/µL at presentation), including 2 patients with CNS-only relapse. Ten patients (27%) proceeded to allogeneic SCT in first remission. The addition of inotuzumab increased the 3-year RFS rate from 74% to 90% (p=0.06) and 3-year OS rate from 82% to 100% (p=0.01).¹²⁵ Inotuzumab was the only factor independently associated with improved RFS and OS by multivariate analysis.¹²⁵ Acknowledging the limitations of this analysis, further confirmation of these findings is warranted. A randomized study of Hyper-CVAD with sequential blinatumomab, with or without inotuzumab, is ongoing which will allow for a more robust assessment of the potential benefit of inotuzumab in this context (NCT02877303). The lower dosing strategy of inotuzumab in the Hyper-CVAD and blinatumomab treatment schema contrasts with the inotuzumab dosing utilized in the Alliance 041501 trial (NCT03150693). This trial randomized patients 18–39 years of age with Ph-negative ALL to receive the pediatric-inspired backbone of CALGB 10403 with or without 2 cycles of inotuzumab consolidation (1.5 mg/m²/cycle; total cumulative dose: 3.0 mg/m²). Two hundred twenty-seven patients (14% with CNS-2/3 disease, 49% with BCR::ABL1-like ALL) were treated. Overall, 87% achieved CR. At a median follow up of 28 months, the 3-year EFS and OS rates were similar regardless of receipt of inotuzumab. The 3-year EFS rate (primary endpoint) was 69% (95%CI: 59–81%) and 3-year OS rate was 80% (95%CI: 71–89%) for the inotuzumab group compared to 67% (95%CI: 57–78%) and 80% (95%CI: 72–90%) for the control group. Twelve grade 5 adverse events occurred during consolidation in the inotuzumab arm compared to only three in the control arm, largely due to sepsis (n=8) or hepato-biliary complications in the setting of infection (n=2), resulting in suspension of the study.¹²⁶

Table 3.

Prospective Studies in Pediatric and Young Adults with Ph-negative ALL Incorporating Blinatumomab and/or Inotuzumab Ozogamicin in the Frontline Setting

Clinical Trial	MDACC (n=75)125	GIMEMA LAL2317 (n=149)214	HOVON-146 (n=71)127	ECOG 1910a (n=112)32	AALL1731a (n=718)130	A041501a (n=111)126
Treatment Schema	HCVAD ± InO → blinatumomab x 4 cycles	Pediatric backbone plus blinatumomab consolidation x 2 cycles	Pediatric backbone plus blinatumomab (pre-phase, consolidation, intensification)	Consolidation chemotherapy ± blinatumomab 2–4 cycles	Consolidation chemotherapy ± blinatumomab x 2 cycles	C10403 regimen ± InO consolidation
Median age, (range) years	33 (18–59)	41 (18–65)	53 (18–70)	51 (30–70)	4 (1–10)	27 (18–39)
CR/CRi rate (%)	100	88	95	100	100	93
MRD negative rate (%)	95 (76% by NGS)	93	91	100	90	81
Median follow up	44 months	37.5 months	43 months	43 months	2.5 years	28.3 months
Survival rate (%)	90% (3-year)	71 (3-year)	76 (4-year)	85 (3-year)	96 (3-year DFS)	80 (3-year)
Allogeneic SCT—n. (%)	24 (32)	NA	26 (37)	22 (20)	NA	36 (13)

HCVAD: hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; InO: inotuzumab ozogamicin; CR: complete remission; CRi: complete remission with incomplete hematologic recovery; MRD: measurable residual disease, by multiparameter flow cytometry; SCT: stem cell transplantation; DFS: disease-free survival; NA: not reported;

^aOutcomes data for patients randomized to blinatumomab or inotuzumab containing arms only

The optimal approach of incorporating blinatumomab into various treatment schemas for patients with newly diagnosed B-cell ALL continues to be explored. The HOVON group added blinatumomab during a pre-phase course, in addition to consolidation and intensification courses of a pediatric-inspired protocol in adults up to 70 years of age (median age 53 years) with both Ph-negative and Ph-positive B-cell ALL in an ongoing phase 2 study.¹²⁷ Among 71 patients (26 with Ph-positive ALL) treated, the CR rate was 95% and MRD-negativity (sensitivity 10⁻⁴) rate 91% after the first blinatumomab consolidation cycle. With a median follow-up of 43 months, the 4-year EFS rate was 57% and the 4-year OS rate was 76%. Among patients ≤60 years of age, the 4-year OS rate was 86%, while outcomes were worse in patients 61–70 years of age (2-year OS rate: 50%).¹²⁷ The GIMEMA LAL2317 study evaluated blinatumomab consolidation with a pediatric-inspired chemotherapy backbone in patients up to 65 years of age (median age 41 years) with Ph-negative B-cell ALL.¹²⁸ One hundred thirty-two of the 149 patients enrolled (89%) achieved CR, including 93% who achieved MRD-negativity after the first course of blinatumomab. The 3-year OS rate for patients 18–40 years was 77%, and 72% for those 41–55 years, outcomes superior to historical results with chemotherapy alone. The 3-year OS rate for patients >55 years was 51%.¹²⁸ The GRAALL investigators found a similar benefit with the addition of blinatumomab consolidation to a pediatric-inspired regimen.¹²⁹ Compared to a historical cohort using the same chemotherapy backbone (n=104), patients who received blinatumomab with consolidation (n=94) had significantly higher rates of MRD-negativity, lower rates of relapse (2.5-year cumulative incidence of relapse (CIR): 20% versus 41%) and superior DFS (2.5-year DFS rate: 72% versus 54%).¹²⁹

The E1910 study confirmed the benefit of blinatumomab in patients with newly diagnosed Ph-negative B-cell ALL who were MRD negative in first CR. Among 488 patients aged 30–70 (median, 51 years) treated with a pediatric-inspired regimen, 224 who achieved MRD-negative CR after 2–3 courses of induction/consolidation were randomized to receive consolidation chemotherapy with or without the addition of blinatumomab (up to 4 courses).³² The median OS among patients randomized to receive blinatumomab has not been reached, compared to 71.4 months with chemotherapy alone (p=0.0003). Similar to the experience of the HOVON and other groups, the survival benefit of blinatumomab was largely restricted to patients <55 years of age, perhaps due to a higher rate of blinatumomab discontinuation in the older population. Another phase 3 trial in pediatric patients with standard-risk B-cell ALL randomized patients to consolidation chemotherapy with or without 2 courses of blinatumomab.¹³⁰ The addition of blinatumomab resulted in a significant improvement in 3-year DFS rate (96% versus 88% with chemotherapy alone; p<0.001).¹³⁰ Severe adverse events were rare, but an increased risk of infectious complications was observed in patients in the blinatumomab arm.

The outcomes of adults with Ph-negative B-cell ALL are improving with the incorporation of blinatumomab consolidation in the frontline setting. Utilization of blinatumomab rather than cytotoxic chemotherapy has resulted in improved outcomes compared to historical controls in both adult and pediatric patients. Studies optimizing the incorporation of blinatumomab with various chemotherapy backbones and incorporating inotuzumab ozogamicin into this treatment setting are ongoing.

5.2. Older ALL

The outcomes of patients ≥ 60 years with Ph-negative ALL have been historically poor, with long-term survival rates of only 10–20% with intensive chemotherapy. While patients in this age group account for only 20% of ALL cases, they make up approximately 50% of all ALL-related deaths.^16,20,131 These outcomes are due to a poor tolerance to chemotherapy highlighted by high rates of mortality during induction and in CR, as well as higher prevalence of adverse-risk disease features.^16,131–134 Treatment schemas designed for older ALL have historically reduced toxicity by reducing the chemotherapy dosing. Ongoing studies in older ALL are working to strike the balance of improving efficacy with the incorporation of antibodies (blinatumomab, inotuzumab) while improving toxicity by reducing the overall chemotherapy exposure (Table 4). The mini-Hyper-CVD and inotuzumab combination +/− blinatumomab omits doxorubicin and significantly reduces the doses and duration of traditional chemotherapy agents (4 courses instead of 8), relying on the added activity of inotuzumab and blinatumomab.^15,135 Maintenance is also shortened to 16 courses overall composed of 12 total courses of POMP and 4 of blinatumomab administered in an alternating fashion (1 blinatumomab course given after every 3 courses of POMP). With a median follow-up of 121 months (95%CI: 61–129), a CR rate of 99% and MRD-negativity rates of 93% by MFC and 94% (n=16/17) by NGS was reported among 83 patients treated (median age 67 years).¹³⁶ Among those evaluable, 7/48 (14%) had CRLF2 alterations and 25/64 (39%) had TP53 mutations. The median PFS was 47 months (95%CI: 22–71) and 5-year PFS rate was 46%. The median OS was 62 months (95%CI: 22=72) and 5-year OS rate was 50%. The 5-year CR duration rate was 79% and median CR duration has not been reached. Five patients (7%) proceeded to allogeneic SCT in CR1.¹³⁶ Six patients (7%) developed sinusoidal obstruction syndrome (SOS), one of which occurred after allogeneic SCT.¹³⁶ Compared to a historical cohort treated with an age-adjusted Hyper-CVAD regimen, treatment with the mini-Hyper-CVD-inotuzumab +/− blinatumomab schema demonstrated an improvement in 3-year OS rate of 63% versus 34%.¹³⁷ Despite significant dose reductions with the mini-Hyper-CVD-inotuzumab +/− blinatumomab regimen, 38 patients (46%) died in remission.¹⁵ An age-dependent decline in survival has been observed, driven largely by higher rates of death in remission in patients ≥70 years of age. This coupled with observation that patients 60 years and older, particularly those with TP53 mutations have an increased cumulative risk of therapy-related myeloid neoplasms of 20–25%, led to an amendment to evaluate a chemotherapy-free approach of inotuzumab and blinatumomab in patients ≥ 70 years of age.^64,138 Fourteen patients with median age 76 years (range, 65–84) have been treated thus far, including 6/13 patients (46%) with high-risk cytogenetics and seven (50%) with a TP53 mutation. Complete remission was achieved in 12 patients (86%) and one patient achieved CRi (7%) for an overall response rate (ORR) of 93%. All 13 responding patients achieved MRD-negativity by MFC and 11/12 (92%) by NGS.¹³⁸ After a median of 15 months (95%CI: 2.3–31 months), the 1-year PFS and OS rates were 64% and 73%, respectively.¹³⁸ The Alliance A041703 study evaluated a similar approach in patients 60 years and older with newly diagnosed Ph-negative ALL.¹³⁹ In this trial, patients received induction with fractionated inotuzumab (1.8 mg/m² in cycle 1; 1.5 mg/m² in cycle 2), followed by up to 5 cycles of blinatumomab consolidation. Among 33 patients treated, 32 (96%) achieved a response, including 85% who did so after induction with inotuzumab alone. The 1-year EFS rate was 75% and OS rate 84%. Nine relapses (27%) and two deaths (6%) in remission have been reported.¹³⁹ In the INITIAL-1 study, newly diagnosed patients greater than 55 years received induction with dexamethasone and fractionated inotuzumab (1.8 mg/m² in cycle 1; 1.5 mg/m² in cycles 2–3), followed by up to 6 cycles of age-adjusted chemotherapy.¹⁴⁰ All 43 treated patients achieved CR/CRi, and 71% achieved MRD-negativity (sensitivity 10⁻⁴) after inotuzumab induction. Only one patient developed non-fatal SOS. The 3-year OS rate was 73%. The EWALL-INO study evaluated inotuzumab-based induction, followed by chemotherapy consolidation and maintenance in older ALL.¹⁴¹ Among 131 treated patients, 90% achieved CR/CRi after 2 courses of induction. The 2-year OS rate was 54%.

Table 4.

Prospective Studies in Older Adults with Ph-negative ALL Incorporating Blinatumomab and/or Inotuzumab Ozogamicin in the Frontline Setting

Clinical Trial	MDACC (n=83)136	INITIAL-1 (n=43)140	EWALL-INO (n=131)141	A041703 (n=33)139	SWOG 1318 (n=29)142	GMALL-Bold (n=50)143
Treatment Schema	Mini-HCVD + InO ± Blinatumomab	InO x 3 cycles→ chemotherapy	InO x 2 cycles→ chemotherapy	InO x 2 cycles → Blinatumomab x 2–4 cycles	Blinatumomab x 4–5 cycles→POMP maintenance	Chemotherapy→ blinatumomab x 3 cycles
Median age, (range) years	67 (60–88)	64 (56–80)	68 (55–84)	71 (60–84)	75 (66–84)	66 (56–76)
CR/CRi rate (%)	99	100	90	97	66	85
MRD negative rate (%)	93	71	81	NA	92	82
Median follow up	121 months	2.7 years	15 months	22 months	3.14 years	757 days
Survival rate (%)	50 (5-year)	73 (3-year)	54 (2-year)	84 (1-year)	37 (3-year)	67 (3-year)
Allogeneic SCT—n. (%)	5 (7)	NA	11 (9)	NA	1	3 (6)
Relapse—n. (%)	12 (14)	NA	29 (22)	9 (27)	NA	6 (12)
SOS—n. (%)	6 (7)	1 (2)	3 (2)	1 (3)	NA	NA
Total Ino Dose	2.7 mg/m2	4.8 mg/m2	2.8 mg/m2	3.3 mg/m2	NA	NA

HCVD: hyperfractionated cyclophosphamide, vincristine, dexamethasone; InO: inotuzumab ozogamicin; POMP: prednisone, vincristine, 6-mercaptopurine, methotrexate; CR: complete remission; CRi: complete remission with incomplete hematologic recovery; MRD: measurable residual disease, by multiparameter flow cytometry; SCT: stem cell transplantation; SOS: sinusoidal obstructive syndrome; NA: not reported;

^aOne case since amendment reducing InO to reduced, fractionated dose

The SWOG 1318 studied up to 5 total cycles of blinatumomab induction/consolidation followed by POMP maintenance in patients 65 years and older with newly diagnosed ALL.¹⁴² The CR/CRi rate among 29 patients treated was 66%, and the 3-year OS and DFS rates were both 37%.¹⁴² In the GMALL BOLD study, 4 cycles of blinatumomab were added to a low-intensity chemotherapy backbone in patients >55 years of age.¹⁴³ Compared with historical data from the GMALL chemotherapy-only regimen, the addition of blinatumomab resulted in significantly higher rates of MRD-negativity (82% versus 55%; p=0.006) and trends towards superior 3-year OS rates (67% versus 49%; p=0.08) and 3-year remission duration rates (83% versus 58%; p=0.055).¹⁴³

An ongoing single-center study (NCT05707273) is evaluating the use of CAR-T cell therapy for consolidation in patients 55 years and older with newly diagnosed B-cell ALL who are not planning to proceed to allogeneic SCT. Patients who have achieved CR after any treatment were eligible and received bridging with low-intensity therapy prior to lymphodepletion and CAR-T cell infusion. Fourteen patients including 11 (79%) who received blinatumomab with their initial treatment (median age 68 years; range, 55–79 years) were treated.¹⁴⁴ Thirteen of 14 patients were in MRD-negative CR prior to lymphodepletion. At a median follow up of 244 days, one patient with Ph-positive disease developed molecular relapse after 6 months, while the remaining 13 patients are in ongoing MRD-negative CR. No deaths have been reported, and no patients developed Immune effector cell-associated neurotoxicity syndrome (ICANS) or grade ≥2 cytokine release syndrome (CRS).¹⁴⁴ Consolidation with CAR-T therapy may be considered to improve outcomes in older patients unable to proceed to allogeneic SCT.

The Golden Gate study (NCT04994717) is an ongoing randomized phase 3 study evaluating low-intensity chemotherapy with or without blinatumomab (given during induction and consolidation) in patients with newly diagnosed B-cell ALL ≥55 years of age, or ≥ 40 years who are otherwise unfit for intensive chemotherapy.¹⁴⁵ Unlike the E1910 trial, this study is evaluating blinatumomab as part of the induction, consolidation, and maintenance (7 cycles) phases and is shortening the traditional maintenance to 12 cycles of POMP. Another ongoing randomized study in older patients is comparing mini-Hyper-CVD plus inotuzumab and blinatumomab to age-adjusted Hyper-CVAD with blinatumomab (NCT05303792).

Incorporation of antibodies including inotuzumab ozogamicin and blinatumomab into frontline therapy for older patients has improved the tolerability of multiagent therapy by avoiding the toxicities of cytotoxic chemotherapy. MRD monitoring by NGS can delineate high-risk patients who may benefit from allogeneic SCT in CR1. An increased risk of developing therapy-related myeloid neoplasms has been observed in patients ≥ 60 years of age and in those with TP53 mutations. These patients may particularly benefit from the use of antibodies and CAR T-cell therapy rather than cytotoxic chemotherapy agents. Patients 70 years and older still represent a group prone to toxicity; therefore, reliance on targeted agents and potentially CAR-T cell therapy is an ongoing area of research in this population.

6. T-cell ALL

T-cell ALL constitutes approximately 10–25% of ALL diagnoses and is composed of 3 major subsets: thymic, mature, and early. These subsets differ by variations in immunophenotypic and biologic features. ETP-ALL is a unique subtype of early T-ALL with some features similar to acute myeloid leukemia (AML) at the cytogenetic and molecular levels. Near ETP-ALL has also recently been described, with an immunophenotype similar to that of ETP-ALL except for high CD5 expression.⁵⁵ Patients with ETP-ALL have a poor prognosis overall including high rates of refractory disease, and should be referred to allogeneic SCT in first remission.^{54,55,57,73,146} In contrast to B-cell ALL, little progress has been made in the expansion of novel and effective treatments for T-cell ALL. Nelarabine, a prodrug of 9-β-arabinofuranosylguanine (ara-G) with selective activity against T-lymphoblasts, was FDA approved in 2005 and is the only therapy specifically approved for the treatment of T-cell ALL. The randomized Children’s Oncology Group (COG) AALL0434 trial reported an improvement in DFS with the addition of nelarabine to a frontline pediatric-inspired regimen in patients 31 years and younger with T-cell ALL.³⁹ The benefit observed by adding nelarabine to the regimen varied based upon the methotrexate and pegylated asparaginase (peg-asparaginase) schedule. Among patients treated with Capizzi-style methotrexate plus peg-asparaginase, the 5-year DFS rate was 87%, compared to 91% with the addition of nelarabine. On the other hand, the 5-year DFS rate among patients who received high-dose methotrexate with fewer overall doses of peg-asparaginase was 78% without nelarabine, compared to 86% with nelarabine. Patients who received a greater number of peg-asparaginase doses (delivered to those receiving the Capizzi-style methotrexate) had improved DFS overall, questioning the benefit of nelarabine in this setting. The rate of isolated CNS relapse was significantly reduced among patients who received nelarabine compared to those who did not (1.3% ± 0.63% versus 6.9% ± 1.4%; p=0.0001).³⁹

Nelarabine has also been added to the Hyper-CVAD regimen for patients with newly diagnosed T-cell ALL and T-cell acute lymphoblastic lymphoma (T-LBL).¹⁴⁷ Adding nelarabine alone did not significantly improve OS, therefore the treatment schema was modified to include peg-asparaginase and later, venetoclax due to pre-clinical studies illustrating the potential utility of the BH3-mimetics venetoclax and navitoclax in the treatment of ETP-ALL.^40,148–150 At a median follow up of 24.4 months (95%CI: 17.7–30.9), among 46 patients treated with this combination, the 2-year PFS rate was 88% compared to 64% (p=0.003), and the 2-year OS rate was 88% compared to 74% without the addition of peg-asparaginase/venetoclax to the Hyper-CVAD and nelarabine regimen.¹⁵¹

A multicenter phase 2 study of venetoclax combined with homoharringtonine, low-dose cytarabine, and G-CSF (HAG) reported a CR/CRi rate of 83% in 31 patients with ETP-ALL. After a median follow up of 15.6 months, 16 patients (53%) have proceeded to allogeneic SCT. The 1-year OS rate was 89%.¹⁵² In addition to novel drugs, CAR T-cell therapy is actively being investigated in T-cell ALL.^153,154 CAR T-cells targeting CD7 have been developed to overcome fratricide with several different methods including the use of an anti-CD7 protein expression blocker which allows for synthesis of CD7 but preventing membrane expression, reducing surface expression of CD7 through epitope masking or intracellular sequestration.^154,155 Recently, a phase 1/2 trial of naturally selected CD7 CAR-T cells in patients aged 2–70 years with relapsed/refractory T-cell ALL (n=35) or T-cell LBL (n=25) demonstrated a MRD-negative CR rate of 96% and 2-year OS rate of 63%. The product was shown to be well tolerated overall, including grade 3–4 CRS in seven patients (12%) and grade 4 ICANS in one patient.¹⁵⁴ A retrospective analysis of 75 patients (median age 12 years; range, 2–43 years) who received donor-derived CD7 CAR T-cell therapy as part of the phase 1 (ChiCTR2000034762) or phase 2 trial (NCT04689659) reported a 24-month EFS rate of 26% (95%CI: 17–41) and OS rate of 29% (95%CI: 19–45).¹⁵⁶ Patients had received a median of four (range, 2–10) prior lines of therapy, 15% had CNS disease, 55% had non-CNS extramedullary disease (EMD), and the median bone marrow blast percentage was 5.77% (range, 0–87.99). Consolidation with allogeneic SCT was significantly associated with superior EFS on multivariate analysis (p=0.035). ¹⁵⁶

T-cell ALL is a distinct entity for which treatment heavily relies on traditional chemotherapy. Emphasis on pegylated asparaginase and incorporation of venetoclax has demonstrated utility, particularly in patients with ETP-ALL. Clinical trials with novel CAR T-cell products are ongoing.

7. Special Considerations

7.1. Burkitt Leukemia/Mature B-cell ALL

Burkitt leukemia, characterized by t(8;14), t(8;2), and t (8; 22) resulting in MYC rearrangement, is a rare subtype of B-cell ALL that responds to high-intensity chemotherapy. The addition of rituximab was shown to improve OS in patients with Burkitt leukemia and is therefore a mainstay of therapy in addition to intensive chemotherapy.^35,157,158 Given the high sensitivity of this disease to intensive therapy, the Hyper-CVAD regimen has served as the standard of care for Burkitt’s disease for a number of years, however there is interest in understanding whether less intensive therapies may be as effective. Dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) with rituximab (R) is one regimen that has proven to be highly effective, with 1 study of 30 young patients (median age 33 years) with Burkitt Lymphoma reporting a 7-year OS rate of 100%.¹⁵⁹ Low- and intermediate-risk disease (no marrow or CNS involvements) comprised 90% of patients in this study. A large multi-center study demonstrated a 3-year PFS rate of 64% and 3-year OS rate of 70% with DA-EPOCH-R among 641 patients (median age: 47 years; range, 18–88).³⁸ Patients 40 years and younger benefited from intensive therapy with Hyper-CVAD compared to other intensive regimens such as CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) or DA-EPOCH-R, whereas older patients (≥60 years) suffered more toxicity with Hyper-CVAD compared to the less intensive DA-EPOCH-R.³⁸

Burkitt leukemia represents a chemotherapy-sensitive subset in which intensive therapy with Hyper-CVAD may be considered for younger patients and those with less favorable outcomes including those with CNS disease and marrow involvement compared to less intensive alternatives such as DA-EPOCH. Burkitt cells express bright CD19 and CD22, therefore investigation of blinatumomab and inotuzumab in Burkitt Leukemia therapy is warranted.

7.2. Philadelphia-like (BCR::ABL1-like) ALL

Philadelphia-like (Ph-like), or BCR::ABL1-like ALL has genetic expression similar to Ph-positive ALL but lacks the classic BCR::ABL1 translocation.^7,67 BCR::ABL1-like ALL accounts for 11–14% of childhood ALL, 20–25% of AYA ALL, and 15% of adult ALL. It is more prevalent among Hispanic patients.^{67,69,160,161} BCR::ABL1-like ALL is associated with GATA3 polymorphism,¹⁶² and over 50% have CRLF2 rearrangement or overexpression.^{68–70 22–25} Activating Janus kinase (JAK) mutations are observed in approximately half of the cases with CRLF2-rearrangement, and are associated with a poorer prognosis.⁶⁸ Patients with CRLF2/JAK altered ALL have poor outcomes with standard chemotherapy, including lower rates of MRD-negativity and long term survival rates of 20%–30%. Allogeneic SCT in first remission is therefore the goal of therapy for these patients.^69,161,163 Approximately 20% of patients with BCR::ABL1-like ALL have ABL1 or PDGFR translocations which may benefit from the addition of BCR::ABL1 TKIs to their therapy.⁶⁹ Leukemic cell lines with expression of various kinase genes have shown some sensitivity to commercially available TKIs including dasatinib (ABL1, ABL2, CSF1R, PDGFRB fusions), ruxolitinib (EPOR, IL-7R, JAK2 rearrangements), and the ALK inhibitor crizotinib (ETV6-NTRK3 fusion) warranting future studies incorporating these targeted therapies.^68,71,72

Blinatumomab demonstrated effectiveness in patients with BCR::ABL1-like ALL in the phase 3 TOWER study, as did inotuzumab in the phase 3 INO-VATE study, overcoming the effect of BCR::ABL1-like alterations.^22,164 The incorporation of blinatumomab and inotuzumab into frontline therapy in BCR::ABL1-like ALL may abrogate its negative impact and further improve the ouctomes.^122,123,163 Early phase 1 results of venetoclax plus chemotherapy in frontline BCR::ABL1-like ALL are promising.¹⁶⁵

Philadelphia-like, or BCR::ABL1-like ALL is a high-risk subset characterized by poor rates of MRD-negativity and dismal outcomes. Incorporation of novel therapies including inotuzumab, blinatumomab and venetoclax may improve outcomes.

7.3. Mixed Phenotype Acute Leukemia and KMT2A rearranged ALL

Mixed phenotype acute leukemia (MPAL) is defined by the presence of cells expressing both lineage-specific myeloid and T- or B-lymphoid markers.⁵² (Supplemental Table 2). In cases where two separate blast populations are observed, each population individually should meet the definition for either a B, T, or myeloid leukemia.⁵¹

There is no standard therapy for patients diagnosed with MPAL. The limited available data suggest that an “ALL–like” or hybrid (ALL/AML) regimen followed by allogeneic SCT may be advisable.^166,167

KMT2A-rearranged ALL is a high-risk ALL associated with poor outcome when treated with traditional chemotherapy approaches.¹⁶⁸ Adding one course of blinatumomab to standard chemotherapy in infants with KMT2A-rearranged B-ALL was associated with a 2-year survival rate of 93%, compared to 66% with historical protocols.³¹ The Children’s Cancer and Leukaemia Group (CCLG) also added one course of blinatumomab to reduced cytotoxic chemotherapy consolidation courses and reported an MRD-negative (MRD <0.01%) CR rate of 93% among 27 infants with KMT2A-rearranged B-ALL, a 2-year OS rate of 93% and 2-year EFS rate of 78%.¹⁶⁹ Given the target for blinatumomab is CD19, lineage switch is a concern.¹⁷⁰ Novel therapies, including the menin inhibitors have shown single-agent activity in KMT2A-rearranged acute leukemias.¹⁷¹ Studies combining menin inhibitors and blinatumomab in KMT2A-rearranged ALL are of interest.

Mixed phenotype acute leukemia is a rare subtype of leukemia for which no standard of care exists. Recent data in infants with KMT2A-rearrranged ALL have demonstrated significant improvement with the utilization of blinatumomab. Clinical trials combining blinatumomab with menin inhibitors are warranted.

7.4. CNS Prophylaxis and Management of CNS relapses

The CNS serves as a sanctuary site for ALL cells, therefore prophylaxis against CNS disease is a necessary component of ALL treatment. While CNS involvement at diagnosis is only observed <10%, the risk of CNS relapse is nearly 75% without CNS prophylaxis.^45,172,173 CNS directed agents include high-dose methotrexate, high-dose cytarabine, and dexamethasone, all of which can penetrate the CNS and as a result make up the backbone of systemic CNS prophylaxis. Despite adequate penetration, these agents alone are unable to eradicate lymphoblasts in the CNS; therefore, IT chemotherapy with methotrexate or cytarabine are also added to prevent CNS disease. Depending upon the treatment backbone and anticipated risk of CNS disease, patients may receive anywhere from 8–15+ doses of prophylactic IT chemotherapy doses throughout therapy.^34,35,38,114 With effective IT and systemic therapy, prophylactic cranial irradiation has been successfully eliminated from standard ALL CNS prophylaxis. Doing so prevents radiation-associated neurologic and cognitive dysfunction and reduces the risk of secondary cancers, therefore improving long-term quality of life of survivors.^45,113,172

Patients who present with CNS disease (mostly of the leptomeninges) at diagnosis are treated with a standard chemotherapy backbone and enhanced IT treatment. Patients receive triple IT therapies (cytarabine, methotrexate, hydrocortisone) twice weekly until blast clearance in the spinal fluid. At that time, IT treatment continues on a less frequent basis. Patients with CNS involvement at the time of diagnosis have a slightly inferior, if not identical, survival to the CNS-negative cohort of patients.^45,174–176

Moving away from intensive chemotherapy and toward lower-intensity chemotherapy backbones with the integration of blinatumomab and inotuzumab into frontline therapy may result in the re-emergence of CNS relapses. Given the omission/reduction of CNS-directed chemotherapy and the inadequate penetration of targeted drugs into the CNS, additional IT chemotherapy is warranted with the use of low-intensity therapies.^15,34

Salvage treatment regimens should incorporate systemic chemotherapy since most isolated CNS relapses may precede systemic relapses.^173,177 Systemic therapy should include CNS penetrating agents (high-dose methotrexate, cytarabine) in addition to incorporating IT administration. Our practice is to administer IT therapy twice a week until CNS clearance, then weekly for 4–8 weeks, then every other week for 4–8 doses, then monthly to complete a total of about 22 ITs. Radiation therapy can be complementary to IT therapies, used for patients with targetable lesions (i.e. cranial nerve involvement), or reserved for instances of intrathecal failure¹⁷⁷.

CAR T-cell therapy has also demonstrated efficacy and tolerability in patients with CNS disease in the R/R setting. Among 48 patients with R/R B-cell ALL with CNS disease, 85% achieved CNS remission and the 12-month cumulative incidence of relapse (CIR) in the CNS was 11%.¹⁷⁸ Nine patients (19%) experienced grade ≥3 CRS and 23% grade ≥ 3 neurotoxicity. Neurotoxicity was associated with a higher CNS disease burden at baseline.¹⁷⁸ The results of a compiled dataset from five clinical trials reported a CR rate of 97% among 66 patients with CNS disease treated with tisagenlecleucel or huCART19.¹¹⁵ Thirteen patients (20%) experienced grade ≥3 CRS and 8 (12%) experienced grade ≥3 neurotoxicity.¹¹⁵ Trials integrating frontline consolidation with CAR T-cells in high-risk patients for CNS relapse are planned.

Prevention of CNS disease in patients with ALL relies on the combination of IT and systemic therapy. Replacement of traditional chemotherapy agents with antibodies has led to increased rates of CNS relapses, requiring an increase in IT doses and incorporation of CNS-directed chemotherapy courses in patients at higher risk of CNS relapse. Management of CNS disease relies on the combination of intrathecal and systemic therapy. Recent data have demonstrated the utility and safety of CAR T-cell therapy for CNS ALL.

8. Monitoring Measurable Residual Disease and Its Management

The presence of MRD has become one of the most important prognostic markers in ALL and also carries therapeutic implications. Various techniques including MFC, RT-PCR, and NGS with different levels of sensitivity are currently available to evaluate MRD in ALL.⁵² MFC immunophenotyping has a short turnaround time, is widely available, and typically utilized in patients with Ph-negative B-cell ALL and T-ALL. Its main disadvantage is limited sensitivity (10⁻⁴; about 1 log less than molecular methods). Some ≥8-color MFC assays have improved sensitivity, to 10⁻⁵, with adequate cellular input. RT-PCR achieves sensitivity of 10⁻⁴ to 10⁻⁵ and is routinely utilized in Ph-positive ALL quantifying BCR::ABL1 mRNA transcripts. RT-PCR is also utilized to quantify MRD in patients with Ph-negative B-cell ALL and T-ALL through allele-specific oligonucleotides which detect unique sequences of the junctional regions of rearranged immunoglobulin (IG) or T-cell receptor (TR) genes.^52,179 NGS-based assays that also use IG/TR genes for quantification with a sensitivity of 10⁻⁶ have recently been developed.^180,181 Most investigators agree on the importance of MRD assessment at different milestones, including at CR achievement, 3–4 months into therapy, and every 3 to 6 months thereafter.

Given the high-sensitivity of the NGS assay compared to standard MFC, the rate of discordance between the two assays as well as the prognostic role of MRD-positivity by NGS have been evaluated.¹⁸¹ Among 74 patients with newly diagnosed Ph-negative ALL, 46% of patients who achieved MRD-negativity by MFC were MRD-positive by NGS. The 5-year CIR among patients with MRD-negativity by NGS at the time of CR was 0% and the 5-year OS was 90%, supporting the use of a highly sensitive assay to evaluate MRD in the frontline setting. Among 110 patients with Ph-negative B-cell ALL, the achievement of MRD-negativity by NGS was associated with improved 2-year RFS rates when evaluated at 1.5 months (100% versus 69%, p=0.03), 3 months (84% versus 60%, p=0.03), and 6 months (88% versus 50%, p<0.001) after start of therapy.¹⁸² Patients with high-risk features who achieve early MRD-negativity have an improved 2-year RFS rate (100% versus 38%, p=0.01). Those who remain MRD positive benefit from allogeneic SCT (2-year RFS rate: 100% versus 20%, p=0.003).¹⁸² Utilizing NGS allows for a more accurate MRD assessment, resulting in improved prognostication, and the possibility to modify treatment as indicated.

Similarly, discordance between monitoring IG/TR versus BCR::ABL1 has been observed in patients with Ph-positive disease. Results from both pediatric¹⁸³ and adult patients have demonstrated approximately 20% of patients with MRD-negativity by PCR for IG/TR and 30% of patients with MRD-negativity by NGS at a sensitivity of 1 × 10⁻⁶ demonstrated detectable BCR::ABL1 by RT-PCR.¹⁸⁰ Among patients who achieved NGS MRD-negativity, the presence or absence of BCR::ABL1 by RT-PCR was not prognostic, suggesting that the persistent BCR::ABL1 transcripts in these patients did not represent true residual lymphoblastic disease. Results from these studies suggest that achieving NGS MRD-negativity can identify patients with a very low risk of relapse, despite persistently detectable BCR::ABL1 transcripts by RT-PCR.¹⁸⁰ In contrast, patients who have detectable MRD by both RT-PCR for BCR::ABL1 and by NGS represents true, clinically significant MRD which may predict for disease relapse.

Blinatumomab was approved for the treatment of patients with MRD-positive disease (≥0.1%) after the BLAST trial demonstrated an MRD-negativity rate of 78% after 1 cycle, translating to an improvement in RFS and OS.^{184 185} Similarly, a phase 2 trial demonstrated an MRD-negativity rate of 73% among 27 patients with MRD positive (≥ 0.01%) disease, resulting in a 3-year RFS rate of 63% and OS rate of 67%.¹⁸⁵ These outcomes compare favorably to the estimated 18-month RFS of 54% reported in the BLAST trial, perhaps due to earlier intervention with blinatumomab (MRD at 10⁻⁴ rather than 10⁻³). A retrospective analysis of 42 patients (31 Ph-negative, 11 Ph-positive) with MRD-positive B-ALL by NGS, demonstrated an NGS MRD-negativity rate of 41% after treatment with blinatumomab (plus BCR::ABL1 TKI for Ph-positive patients).¹⁸⁶ A 2-year RFS rate of 71% and OS rate of 100% was observed in patients who achieved NGS MRD-negativity compared to 25% (p=0.001) and 46% (p<0.001), respectively in those who did not. Among those who did not achieve NGS MRD-negativity with blinatumomab, allogeneic SCT improved the 2-year RFS rate to 63% compared to only 10% among those who did not proceed to allogeneic SCT (p=0.002).¹⁸⁶ Patients who achieve MRD-negativity by NGS after treatment with blinatumomab have excellent long-term outcomes, while those who do not should be considered for CAR T-cell therapy and/or allogeneic SCT.

While not formally approved for use in MRD-positive disease, both inotuzumab and CD19 CAR T-cells have shown promise in this setting. In a phase 2 study, 26 patients with MRD-positive (≥0.01% by MFC or PCR for BCR::ABL1) B-cell ALL were treated with low-dose fractionated inotuzumab (plus BCR::ABL1 TKI for Ph-positive patients).¹⁸⁷ The rate of MRD-negativity was 80% in Ph-negative ALL and 63% in Ph-positive ALL. Six patients (33% of responders) proceeded to allogeneic SCT. The 2-year OS rate was 54%.¹⁸⁷ Real-world data with tisagenlecleucel suggests its benefit in patients with MRD-positivity¹⁸⁸. In a retrospective analysis, 41 patients with low-burden B-cell ALL were treated (defined as MRD-positive disease or CNS-1 or CNS-2 disease). Forty patients (98%) responded. Lower disease burden prior to tisagenlecleucel infusion was associated with a lower rate of grade ≥ 3 CRS compared to those with high-burden disease (10% versus 35%) and superior OS (1-year OS 85% versus 58% with high-burden disease). These data suggest that both inotuzumab and CD19 CAR T-cells may be effective to eradicate MRD in B-cell ALL and provide a rationale to position these therapies earlier in the treatment algorithms to deepen MRD responses and improve long-term outcomes.

Measurable residual disease has become the most important prognostic factor in ALL. Multiple modalities for MRD monitoring exist, with NGS representing the most sensitive assay (1 × 10⁻⁶). When monitoring MRD for Ph-positive ALL, persistent BCR::ABL1 transcripts by RT-PCR alone should not be used to escalate therapy to allogeneic SCT. Follow up testing by NGS should be considered to identify presence of residual lymphoblastic disease. Utilizing NGS for MRD monitoring may allow for optimal identification of the subset of patients who may benefit from allogeneic SCT in first remission.

9. Salvage Treatments

The rates of complete response after relapse are low with chemotherapy, 30%–40% in first salvage and only 10%–20% in second salvage and beyond.^22,23 After relapse, allogeneic SCT is the goal for cure, however a minority of patients (20%–40%) are able to be successfully bridged to transplant.¹⁸⁹ And even then, the outcomes are poor (potential cure rates 20–30%). Using combinations of chemotherapy with targeted immunotherapy (inotuzumab, blinatumomab, CAR T-cells in low disease burden) may reduce toxicity, improve the rate and depth of responses, increase the proportion of patients bridged to SCT, and therefore increase the overall cure rates.^22,23,190 For patients with refractory T-cell ALL, one might search for ABL1-class fusions, mostly NUP214-ABL1, EML1-ABL1, and ETV6-ABL1, for which treatment with ABL TKIs could be of benefit.

9.1. Anti-CD19 Bi-specific T-cell Engager: Blinatumomab

Blinatumomab was the first BiTE antibody approved, targeting CD3 on T-cells and CD19 on leukemic blasts.^22,184 Blinatumomab is administered as a continuous infusion over the first 4 weeks of a 6-week cycle. The randomized phase 3 TOWER trial demonstrated a significant improvement in overall response (45% versus 30%, p=0.007), molecular remission (<10^–4 blasts) (75% versus 48%), and OS in patients with R/R B-ALL treated with blinatumomab compared to standard of care chemotherapy (median 7.7 months versus 4.0 months; p=0.012, HR=0.71).²² The 4-week blinatumomab continuous infusion can be cumbersome, therefore a SC formulation is being investigated. A phase 1b study evaluating the safety, efficacy, and pharmacokinetics of SC blinatumomab administered at 2 doses: 250 μg once daily for one week followed by 500 μg three times weekly (250/500) and 500 μg once daily for one week followed by 1000 μg three times weekly (500/1000) administered every five weeks is ongoing. These schedules resulted in a response rate of 89%, including MRD-negativity rate of 92% among 27 patients with R/R B-cell ALL.¹⁰² The incidence of grade 3 CRS was 22% and grade 3 neurotoxicity was 23%. After a median follow-up of 14.1 months the median duration of response (DOR) was 5.9 months and OS was 14.5 months for the 14 patients treated with the 250/500 dosing schedule. Median DOR was 12.6 months, and median OS was not reached among 13 patients treated with the 500/1000 dosing schedule. Eleven patients (46%) proceeded to allogeneic SCT after achieving a response with SC blinatumomab.^102,191 The combination of convenience, ease of delivery, and high efficacy achieved with SC blinatumomab could have a significant global impact and may replace the IV formulation.

9.2. Anti-CD22 Antibody-drug Conjugate: Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an ADC comprised of an anti-CD22 antibody linked to calicheamicin, a potent cytotoxic payload. As a single agent, inotuzumab also demonstrated improvement in ORR (88% versus 32%, p<0.0001), MRD-negativity (78% versus 28%, p<0.0001) and OS (median 7.7 months versus 6.7 months, p=0.02, HR=0.77) among patients with B-cell ALL in first or second relapse compared to standard chemotherapy in the randomized phase 3 INO-VATE study.²³ A serious safety signal with inotuzumab was observed in the phase 2 studies, with 23% of patients in a single-center study experiencing SOS, particularly in patients who proceeded to allogeneic SCT and received dual alkylators as part of their conditioning regimen.¹⁹² As a result, modes to mitigate toxicity due to inotuzumab were explored and the administration of inotuzumab was modified from bolus doses of 1.3–1.8 mg/m² given every 3–4 weeks to doses of 0.5 mg/m²–0.8 mg/m² given once weekly, resulting in lower rates of SOS without impacting efficacy.^192,193 With this weekly dosing strategy, the rate of SOS in the INO-VATE trial was 11%, again with an increased risk observed among those receiving a dual-alkylator conditioning regimen.²³ Inotuzumab has also been approved for the treatment of pediatric patients ≥ 1 year with R/R B-cell ALL; however SOS also remains a concern in this population. Results from the ITCC-059 trial reported an SOS rate of 13% among a cohort of 108 patients aged 1–18 years with R/R B-cell ALL, and 20% among those who proceeded to allogeneic SCT after inotuzumab.¹⁹⁴ When evaluating risk factors for the development of SOS, the time from the last inotuzumab dose to allogeneic SCT was the only significant factor identified (p<0.005). Median time from last inotuzumab dose to SCT was 28 days (range, 20–87) among those who developed SOS compared to 55 days (range, 21–182) among those who did not.¹⁹⁴

9.3. Combination Therapies

Survival with single-agent inotuzumab and blinatumomab remained low in R/R ALL: median survival <8 months; overall survival at 2–3 years 25% or less.^22,23 Given their individual activity and lack of cross-toxicity with traditional chemotherapy, a combination of low-intensity mini-Hyper-CVD and inotuzumab +/− blinatumomab was investigated.¹⁹⁵ Inotuzumab was added to the mini-Hyper-CVD regimen initially administered in the bolus fashion, but later amended to the lower fractionated schema delivering 0.9 mg/m² total during course 1 and 0.6 mg/m² total during courses 2–4, plus the addition of ursodiol for SOS prophylaxis. In addition to the modified inotuzumab dosing, the study was later amended to add sequential blinatumomab.¹⁹⁶ An ORR of 83% was reported among 110 patients treated. Nearly half of the population (48%) were able to proceed to allogeneic SCT. After a median follow-up of 48 months, the median OS was 17 months and 3-year OS rate was 40%, both improvements over historical results with the Hyper-CVAD or with what has been reported with either inotuzumab or blinatumomab monotherapy. A landmark analysis at four months demonstrated a 3-year OS of 54% regardless of receipt of allogeneic SCT. Notably, the rate of SOS was 13% with the original bolus inotuzumab dosing, but decreased to just 2% with the modified, weekly dosing schedule (p=0.02), which also distanced the last Inotuzumab dose from a potential SCT.^196,197

Given the tolerability of this regimen and the desire to further improve outcomes, the administration of blinatumomab concurrently with the mini-Hyper-CVD plus inotuzumab regimen has been evaluated. Among 22 patients treated (19 in Salvage 1), the MRD-negativity rates were 95% (18/19) and 94% (16/17) by MFC and NGS, respectively.¹⁹⁸ At a median follow up of 15 months, the 2-year OS rate was 79% and 2-year RFS rate was 76%.¹⁹⁹ This combination regimen was superior to the historical mini-hyper-CVD-inotuzumab with or without sequential blinatumomab overall (1-year OS rate of 90% versus 51%–66%; p=0.006). Among patients treated in first salvage, the 1-year OS rate with concomitant blinatumomab was 94% compared to 63–66% (p=0.08) for the mini-hyper-CVD-inotuzumab with or without blinatumomab, respectively.¹⁹⁷ This strategy may be better than sequential use of these agents either as monotherapy or in sequential combinations and is currently being evaluated in the frontline setting.

9.4. Chimeric Antigen Receptor T-cell (CAR T-cell) Therapies

CAR T-cells are genetically engineered to express binding sites of specific antibodies, therefore targeting malignant cells expressing the appropriate antigen, such as CD19.²⁰⁰

Tisagenlecleucel was the first CAR T-cell approved for R/R B-cell ALL after the results of the ELIANA trial demonstrated promising outcomes (Table 5). Of the 97 patients aged 3–23 years with R/R B-cell ALL treated, 67% achieved a CR.^201,202 The 5-year EFS rate was 42% and 5-year OS was 55%. Multivariate analysis showed that MRD-positivity detected by NGS at 3 months after tisagenlecleucel therapy was associated with inferior EFS and OS.²⁰¹ Grade 3–4 CRS was reported in 49% and Grade 3–4 ICANS in 21%.^201,202

Table 5:

CD19 Chimeric Antigen Receptor (CAR)-T cells in ALL

	Tisagenlecleucel202,215,216		Brexucabtagene Autoleucel190,203		Obecabtagene Autoleucel206,207
Co-stimulatory domain	4–1BB		CD28		4–1BB
Number of patients infused	79	255	55	189	127
Median age (range), years	11 (3–24)	13 (0.4–26)	40 (28–52)	46 (18–81)	47 (20–81)
CR/CRi (%)	82	86	73	90	78
MRD negative rate (%)	98	99	100	79	94
Grade ≥3 CRS/ Grade ≥3 ICANS (%)	48/21	16/9	24/25	11/31	3/8
Median follow up (months)	38.8	13.4	54	11.4	14.1
Median survival (months)	Not reached	NA 12-month OS rate: 77%	26 (16.2–60.4)	Not reached	23.8 (12.9-NR)

CR: complete remission; CRi: complete remission with incomplete hematologic recovery; MRD: measurable residual disease; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; OS: overall survival

Brexucabtagene autoleucel, another CD19 CAR T-cell therapy, led to an ORR of 55% and MRD-negativity rate of 97% among 71 adults (median age 40 years) with R/R B-cell ALL..¹⁹⁰ Longer-term follow up showed better survival with lower disease burden at the time of infusion and among those treated in first salvage compared to later relapse. The median OS was 25.6 months among evaluable patients.²⁰³ Grade ≥3 CRS was reported in 24% of patients and Grade ≥3 ICANS in 25%.¹⁹⁰ A large real-world analysis of brexucabtagene autoleucel across 31 centers in the U.S. included 189 patients (median age 46 years; range, 18–81 years), 42% of whom were in CR (15% MRD negative) at the time of brexucabtagene infusion.²⁰⁴ Patients were heavily pre-treated, 41% had prior allogeneic SCT, 59% had received prior blinatumomab, and 18% had CNS disease. Bridging therapy was administered between apheresis and CAR T-cell infusion to 65% of patients. At Day +28, 151/168 (90%) evaluable patients achieved CR/CRi and 119 (79%) responders achieved MRD-negativity. Among 25 evaluable patients with CNS disease, 22 (88%) had CNS clearance. After a median follow-up of 11.4 moths, the 12-month PFS rate was 48% and 12-month OS rate 63%. Achievement of MRD-negativity by NGS by Day +28 was associated with superior PFS (p=0.0026) and OS (p=0.0098) compared to those who were MRD positive. Receipt of allogeneic SCT prior to brexucabtagene (HR: 0.41; p=0.004) as well as after brexucabtagene (HR: 0.34; p=0.02) were each associated with improved PFS, while receipt of inotuzumab prior to brexucabtagene was associated with inferior PFS (HR: 1.75; p=0.03).²⁰⁴ Grade ≥3 CRS occurred in 11% of patients at a median of 5 days after infusion and grade ≥ 3 ICANS in 31% at a median of 7 days after infusion. Higher disease burden at the time of apheresis was associated with increased risk of Grade 3+ CRS (p=0.006). Ten patients (5.3%) experienced early death within the first 28 days after infusion due to CAR T-related toxicity or infection.²⁰⁴ Utilizing this same database of real-world treated patients, an analysis of 280 patients ≥ 60 years of age demonstrated an increased rate of ICANS in patients ≥ 70 years (77%) compared to those 60–69 years (47%). Grade 1–2 ICANS specifically occurred at a significantly higher rate among patients ≥ 70 years (44% versus 20%; p=0.049), while Grade 3+ ICANS occurred at similar rates regardless of age.²⁰⁵

Obecabtagene autoleucel (Obe-cel) is a novel CD19 CAR T-cell therapy designed with a fast off-rate to reduce immunotoxicity and improve engraftment by reducing the degree of T-cell activation.²⁰⁶ Dose titration and split-dosing were also utilized to optimize the dose delivered based on disease burden and safety. Ninety-nine (78%) of the 127 patients infused in the Phase 1b/2I study achieved a CR/CRi. After median follow-up of 21.5 months, 40% of responders maintained a durable response without an allogeneic SCT. The 12-month EFS rate was 49% and 12-month OS rate 61%. Rates of Grade ≥3 CRS and Grade ≥3 ICANS were 2.5% and 7.5%, respectively.²⁰⁶ Among responders, 84% achieved MRD-negativity (<10⁻⁶) which led to improved outcomes including median DOR of 17.1 months and median OS that has not been reached.²⁰⁷ CAR T-cell persistence was associated with improved EFS, whereas no improvement in outcomes was observed in patients who proceeded to allogeneic SCT.

Progress with CAR T-cell therapy is still needed, as more than 50% of patients who receive CAR T-cell therapy still relapse. Failure of CAR T-cell therapy is thought to be driven by the loss of CD19 surface antigen expression.²⁰⁸ The burden of disease appears to play a role in the effectiveness of therapy, where patients with lower or no detectable disease have the best outcomes.^188,209 Clinical trials evaluating CAR T-cells targeting other or dual epitopes (e.g CD19 and CD22) are ongoing. ^210,211

Incorporating CAR T-cell therapy into the consolidation phase of treatment for patients with high-risk disease is an attractive approach to possibly replace the need for allogeneic SCT. This strategy would allow for a decreased risk of CRS due to low burden of disease, with potentially improved efficacy. However, concerns about optimal CAR T-cell expansion in patients without detectable disease are valid. Clinical trials assessing CAR T-cell therapy as part of consolidation in the frontline setting for high-risk ALL and with persistent or recurrent MRD-positivity are ongoing.

In the absence of a clinical trial, salvage therapy typically consists of combination chemotherapy regimens that incorporate either blinatumomab and/or inotuzumab ozogamicin. The combination of multiagent chemoimmunotherapy with CAR T-cell consolidation followed in specific cases (lack of expansion/persistence and presence of MRD by NGS) by an allogeneic SCT is the best approach for patients with relapsed/refractory disease. Clinical trials optimizing this strategy are ongoing.

10. Conclusions

Significant progress has been made in deciphering the pathophysiology of adult ALL, identifying new disease subsets, assessing the impact of MRD, and developing novel targeted therapies. The incorporation of antibodies and other novel targeted approaches into the frontline regimens to optimize efficacy and decrease toxicities, are promising. Future strategies may lead to 1) the incorporation of multiple available antibodies into one regimen, including newer formulations (e.g. SC blinatumomab); 2) less chemotherapy and a shorter overall treatment duration; 3) the replacement of toxic and myelosuppressive chemotherapy with more targeted agents (e.g blinatumomab and ponatinib in Ph-positive ALL, and blinatumomab and menin inhibitors in KMT2A-rearranged ALL); and 4) the use of sequential CAR T-cell therapies in patients with positive MRD or high-risk disease to hopefully replace allogeneic SCT in this setting. While the efficacy of such strategies is yet to be solidly proven, these combined modalities may very likely increase the cure rates of adults with ALL to levels achieved in pediatric disease.

Figure 1: Treatment Algorithm for Frontline Ph-positive B-cell ALL.

Treatment with blinatumomab and a TKI is recommended for patients with newly diagnosed Ph-positive B-cell ALL. Measurable residual disease (MRD) can be monitored by both PCR for BCR::ABL1 and by next generation sequencing (NGS), however treatment decisions, including allogeneic SCT, should be guided by NGS MRD.

TKI: tyrosine kinase inhibitor; NGS: next generation sequencing; MRD: measurable residual disease; SCT: allogeneic stem cell transplantation

Figure 2: Treatment Algorithm for Frontline Ph-negative B-cell ALL.

Induction and consolidation with an age-adjusted chemotherapy backbone incorporating blinatumomab and/or inotuzumab ozogamicin is preferred. Measurable residual disease (MRD) should be monitored by next generation sequencing (NGS) for the most accurate disease assessment and for consideration of allogeneic stem cell transplantation (SCT). Consolidation with CAR T-cell therapy may be considered in patients with high-risk features who achieve MRD-negativity and as a bridge to allogeneic SCT among patients who are MRD positive.

NGS: next generation sequencing; MRD: measurable residual disease; SCT: allogeneic stem cell transplantation