Adult acute lymphoblastic leukemia: incorporation of recent advances into current treatment strategies

Abstract

Outcomes in B-cell acute lymphoblastic leukemia (ALL) have improved over time due to therapeutic advances, and improved disease monitoring and prognostication. The BCR::ABL1 tyrosine kinase inhibitors (TKIs) were the first targeted therapies to significantly impact the therapeutic trajectory and outcomes of Philadelphia chromosome-positive (Ph-positive) ALL. Similarly, antibodies targeting CD19/20/22 and engineered chimeric antigen receptor (CAR) T-cell immunotherapies have drastically changed the therapeutic landscape and outcomes of B-cell ALL. Incorporation of the bispecific T-cell engager (BiTE) blinatumomab has demonstrated a significant survival advantage in patients with both newly diagnosed Philadelphia chromosome-negative (Ph-negative) and Ph-positive ALL. Inotuzumab ozogamicin, the anti-CD22 antibody drug conjugate (ADC), has also been safely integrated into the frontline treatment backbones in both younger and older patients. CAR T-cell therapy has resulted in durable remissions in relapsed/refractory (R/R) ALL, especially with lower disease burden. CAR T-cell therapy consolidation in the frontline setting is being pursued with the goal of reducing the need for allogeneic stem cell transplantation (alloSCT). Future research is focusing on treatment optimization through replacement of chemotherapy with immunotherapies with the goal of reducing toxicities, minimizing the need for alloSCT, and shortening the intensity and duration of therapy while improving long-term outcomes.

Introduction

The outcomes in newly diagnosed ALL have improved significantly over the past few decades due to improvements in prognostication, measurable residual disease (MRD) monitoring, and the incorporation of targeted therapies into the standard chemotherapy regimens [1, 2]. These advances resulted in cure rates above 80–90% in pediatric ALL [3, 4], but the overall survival (OS) rates in adult ALL have plateaued at 5-year OS rates of 50% [5–11]. This is due to several factors including greater comorbidities and chemotherapy intolerance, an increased rate of adverse genomic characteristics and unfavorable disease characteristics in the adult population [12–15]. The recent utilization of the more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) in the frontline treatment of Philadelphia chromosome (Ph) positive ALL and the advent of therapies such as inotuzumab ozogamicin (InO), blinatumomab, and chimeric antigen receptor (CAR) T-cell therapy targeting cell surface antigens CD22 and CD19 have improved outcomes in adult patients. This review highlights how to best incorporate these and other novel therapies into the treatment of patients with ALL with an emphasis on emerging data presented in 2025.

Treatment approach

The overall treatment approach for patients with ALL is largely driven by the patient age and ALL immunophenotype (i.e. B-cell ALL versus T-cell ALL), historically relying on a combination of cytotoxic chemotherapy agents [2]. We still rely on a backbone of intensive chemotherapy for young patients with Ph-negative B-cell ALL, but are now actively incorporating blinatumomab into consolidation and maintenance. Older patients (≥60 years) are treated by incorporating InO and blinatumomab with low-intensity chemotherapy, or without any chemotherapy (patients ≥70 years) due to treatment-related morbidity and mortality [9], as well as the increased risk of therapy-related myeloid neoplasms (≥60 years and TP53-mutated ALL) [16] (Fig. 1A). Patients with Ph-positive disease are treated with blinatumomab in combination with potent TKIs (e,g. ponatinib), with chemotherapy consolidation added for patients with increased risk of relapse (WBC ≥ 70 ×10⁹/L at presentation) (Fig. 1B). CAR T-cell therapy is being integrated into the frontline treatment for patients with high-risk disease features and those with MRD-positivity, either as a bridge to allogeneic hematopoietic stem cell transplantation (alloSCT) or as definitive consolidation therapy. We utilize next generation sequencing (NGS) at a sensitivity of 10⁻⁶ to dynamically monitor treatment response and determine who may benefit from CAR T-cell and/or alloSCT. Patients with T-cell ALL continue to receive cytotoxic chemotherapy with the incorporation of asparaginase, nelarabine, and venetoclax (Fig. 1C). Novel CAR products are under investigation and are eagerly awaited, particularly for high-risk patients with early T-cell precursor (ETP) ALL.

Fig. 1. MDACC Treatment Algorithms for Patients with Acute Lymphoblastic Leukemia.

A Treatment algorithm for frontline Ph-negative B-cell ALL. Patients should receive treatment with a combination of inotuzumab, blinatumomab, and a chemotherapy backbone depending on age. MRD should be monitored by (NGS for dynamic evaluation of alloSCT. CAR T-cell therapy consolidation is considered for all patients with NGS MRD-positivity and in high-risk patients (low hypodiploidy/near triploidy, KMT2A-rearranged, Philadelphia-chromosome like, TP53^mut) who achieve early MRD-negativity with the goal to prevent the need for alloSCT. Patients who are NGS MRD-positive after CAR T-cell consolidation should pursue alloSCT. B Treatment Algorithm for Frontline Ph-positive B-cell ALL. Treatment intensification with 2 courses of high-dose MTX and Ara-C is added to all patients with a baseline WBC ≥ 70 ×10⁹/L followed by CAR T-cell consolidation. MRD is monitored by both NGS and PCR for BCR::ABL1, however intensification of therapy with allogeneic stem cell transplantation is guided by NGS. Treatment decisions, including alloSCT, should be guided by NGS MRD. C Treatment Algorithm for Frontline T-cell ALL. Patients with T-cell ALL should be treated with combination chemotherapy including peg-asparaginase, nelarabine, and venetoclax. Venetoclax can be stopped once MRD-negativity is achieved except for in patients with ETP ALL. Patients with ETP-ALL should also be considered for alloSCT. AlloSCT is not typically pursued for patients with other subtypes of T-cell ALL unless other high-risk genomic factors are identified. D Treatment Algorithm for Relapsed/Refractory B-cell ALL. Treatment on clinical trial with novel BiTEs or TKIs should be pursued if possible. For patients receiving standard of care, CAR T-cell therapy should be pursued in consolidation. CAR expansion and persistence should be monitored and the decision to pursue alloSCT guided by a combination of salvage status, CAR T-cell expansion and persistence, and NGS MRD, in addition to patient-specific factors. MRD measurable residual disease, NGS next-generation sequencing, alloSCT allogeneic stem cell transplantation, CAR T-cell chimeric antigen receptor T-cell, MTX methotrexate, Ara-C cytarabine, WBC white blood cell, PCR polymerase chain reaction, BiTEs bispecifc T-cell engagers, TKI tyrosine kinase inhibitor.

Younger patients with Philadelphia chromosome-negative B-cell ALL

The long-term follow-up of 295 adolescent and young adult (AYA; 17–39 years) patients treated with CALGB10403 reported a 10-year OS rate of 56% (95% CI: 50.4–62.3), 10-year event-free survival (EFS) rate of 44% (95% CI: 38.2–50.8) and median OS that has not been reached [17]. Achieving MRD-negativity after induction was associated with significantly improved 10-year disease-free survival (DFS) (83% versus 40%; HR: 0.23; 95% CI: 0.09–0.55) and OS rates (85% versus 52%; HR: 0.26; 95% CI: 0.1–0.69). Ph-like disease was a significant predictor for worse OS (HR: 2.08; 95% CI: 1.19–3.65) [17].

Pediatric-inspired regimens and the Hyper-CVAD regimen have both been modernized with the incorporation of blinatumomab and InO into consolidation courses, improving outcomes for Ph-like and other high-risk groups (Table 1). The E1910 trial demonstrated a survival benefit in adult patients (age 30–70 years) who achieved MRD-negativity (46% of total denominator) after a pediatric-inspired induction-consolidation (3 courses of intensive chemotherapy) and received blinatumomab during consolidation compared to patients receiving chemotherapy alone [18]. This benefit was observed among AYA patients as well as those with high-risk molecular features and Ph-like ALL [19, 20].

Table 1.

Clinical trial results incorporating blinatumomab in patients with newly diagnosed Philadelphia chromosome-negative B-cell ALL.

Clinical trial	ECOG 1910a (n = 112)	GRAAL-2014/B-QUESTa (n = 94)	MDACC HCVAD (n = 75)	MDACC Mini-Hyper-CVD (n = 83)	A041703 (n = 33)	MDACC chemotherapy-free (n = 18)
Patient population	Adults 30–70 yrs in MRD-negative (<10−4) CR/CRi after pediatric-inspired induction	Adults ≥18 yrs with HR-ALLb in sustained CR at week 12 (start of consolidation 2)	Adult and pediatric patients ≥14–59 yrs	Adults ≥60 yrs	Adults ≥60 yrs (n = 33)	Adults >70 yrs or ≥60 yrs unfit for chemotherapy
Treatment schema	Consolidation chemotherapy ± 2–4 blinatumomab cycles	Consolidation chemotherapy ± 5 blinatumomab cycles	HCVAD ± InO x 4 cycles → 4 blinatumomab cycles	Mini-Hyper-CVD + InO ± 4 blinatumomab cycles	InO x 2 cycles → 2–4 blinatumomab cycles	Vincr + dex→ 5 blinatumomab + InO cycles
Median age, (range) years	51 (30–70)	34 (18–59)	33 (18–59)	67 (60–88)	71 (60–84)	76 (65–83)
CR/CRi rate (%)	100	100%	100	99	97	94
MRD negative rate (%)	100	72% after consolidation 2	95 (79% by NGS)	93	NA	89 (67% by NGS)
Median follow up	43 months	NA	48 months	121 months	45 months	24 months
DFS rate—blinatumomab vs chemotherapy (time-point)	80% vs 64% (3 yr) (HR: 0.53; 95% CI: 0.32–0.87)	68% vs 48% (5 yr) HR 0.48, 95% CI: 0.31–0.75	83% (4 yr)	46% (5 yr)	48% (3 yr)	51 (2 yr)
OS rate—blinatumomab vs chemotherapy (time-point)	85% vs 68% (3 yr) (HR: 0.41; 95% CI: 0.23–0.73; p = 0.002)	79% vs 54% (5 yr) HR 0.54, 95% CI: 0.32–0.93	91% (4 yr)	50% (5 yr)	59% (3 yr)	50 (2 yr)
Allogeneic SCT—n. (%)	22 (20)	44/50 (88)	24 (32)	5 (7)	5 (15)	2 (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 relapse-free survival, NA not reported.

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

^bHigh risk (HR) defined as: end-of-induction MRD ≥ 10⁻⁴, presence of KMT2Ar, or IKZF1 intragenic deletion (IKZF1del).

Unlike E1910, the Hyper-CVAD-blinatumomab regimen replaces four consolidation courses with blinatumomab, reducing the number of intensive courses from eight to four (50% reduction of intensive chemotherapy) and decreases maintenance from 30 courses to 15 [21]. The regimen has been later modified to add InO every other course (2 even chemotherapy courses and 2 blinatumomab courses; cumulative dose: 2.4 mg/m²) along with further reduction in chemotherapy [21, 22]. Overall, 75 patients with a median age of 33 years (range, 18–59) have been treated with (n = 37) or without (n = 38) the addition of InO [23]. All patients achieved a complete remission (CR), 95% achieved MRD-negativity by multiparameter flow cytometry (MFC) and 76% by NGS [23]. The 4-year EFS and OS rates were 83% and 91%, respectively. The 4-year OS rate was 85% in high-risk ALL and 95% in low-risk ALL. Twenty-four patients (32%) proceeded to alloSCT. The 4-year OS rates for low-risk patients who did or did not proceed to alloSCT were 100% and 97%, respectively. These rates were 90% and 75% in high-risk patients, respectively. Patients who received both blinatumomab and InO had improved 4-year OS and EFS rates; on multivariate analysis, InO was the only significant factor associated with improved OS (HR 12.5; p = 0.02) and EFS (HR: 3.15, p = 0.06) [23]. A propensity score analysis comparing the Hyper-CVAD-blinatumomab +/− InO regimen (n = 55) to Hyper-CVAD (n = 55) demonstrated improvement in the 5-year OS rate (90% versus 63%; p = 0.006) and 5-year EFS rate (86% versus 57%; p = 0.009) [24]. While the E1910 trial demonstrated a survival advantage with blinatumomab in MRD-negative patients, the propensity score analysis demonstrated the benefit of blinatumomab among all-comers. This was observed despite a significant reduction in the chemotherapy intensity and duration, suggesting the replacement of chemotherapy courses with blinatumomab is an effective approach. Overall, these results indicate an advantage with incorporating blinatumomab into the frontline setting as well as the use of InO. This is our current treatment approach at MD Anderson. A randomized trial evaluating Hyper-CVAD plus blinatumomab with or without InO is ongoing (NCT02877303).

While these results are encouraging, it is important to contextualize them within the broader safety experience reported by the cooperative groups. Higher cumulative doses of InO have been associated with increased risk of hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), particularly in patients proceeding to alloSCT. In the Hyper-CVAD regimen in combination with blinatumomab and InO, the cumulative InO dose was limited at 2.4 mg/m², which likely mitigates this risk. Recently, cooperative group trials incorporating antibody-based strategies into frontline therapy, including AALL1732 and Alliance A041501 have reported instances of later toxicities and deaths occurring in remission [25, 26]. These findings underscore the necessity of long-term safety surveillance, particularly as standard chemotherapy agents are reduced and novel agents are incorporated earlier in therapy.

Older patients with Philadelphia chromosome-negative B-cell ALL

The treatment of older patients (≥60 years) with newly diagnosed B-cell ALL has been historically challenging. With such intensive chemotherapy regimen, the CR rates were 60–90%, but the 3-year survival rates were generally <15%. The development of novel treatment regimens incorporating InO and blinatumomab, in lieu of myelosuppressive chemotherapy or agents that are difficult to administer in older adults (e.g., asparaginase), has resulted in significant improvements in clinical outcomes and remains an area of active investigation (Table 1) [27]. The mini-Hyper-CVD-InO and blinatumomab regimen omits doxorubicin and significantly decreases all other chemotherapy doses, relying instead on adding InO and blinatumomab [28]. This regimen led to a CR rate of 99% (MRD-negative: 93%) and 5-year progression-free survival (PFS) and OS rates of 46% and 50%, respectively, among 83 patients treated (median age 67 years; range, 60–88) [9, 29]. However, among the 28 patients aged 70 years or older, 20 (71%) died, of which 17 (85% of deaths) were due to deaths in remission [9]. Furthermore, recent analyses indicate that, in patients ≥60 years, especially those with TP53-mutated ALL, the cumulative risk of therapy-related myeloid neoplasms was 20–25% [16]. As a result, patients >70 years or those ≥60 unfit for chemotherapy receive a chemotherapy-free regimen of Ino-blinatumomab (minimal vincristine-steroids induction) [30, 31]. Eighteen patients (median age 76 years; range, 65–83; 94% >70 years) were treated, including 50% with TP53-muated ALL and 38% with high-risk cytogenetics [31]. Seventeen (94%) achieved a CR/CRi (MFC MRD-negative: 89%); the 2-year EFS and OS rates were 51% and 50%, respectively, with 2 patients (13%) proceeding to alloSCT [31]. The Alliance A041703 trial similarly evaluated a chemotherapy-free regimen of InO and blinatumomab in patients ≥60 years including 49% with NCCN poor-risk genetics [32]. An important difference from our study was the population age: median age 71 years; and about 50% >70 years; versus median age 76 years and 94% >70 years in our study group. Outcomes were similar to the MD Anderson results. Patients with detectable MRD by PCR at any time point had significantly worse EFS and OS compared to those with undetectable MRD. Among those with MRD-negativity after Course 1, the 3-year EFS and OS rates were 52% and 100% compared to 0% for patients with MRD-positivity [33]. These trials indicate the need for improving treatment-related mortality in older and unfit patients and perhaps relying on InO and blinatumomab in this setting. The ongoing phase 3 Golden Gate study (NCT04994717) is randomizing patients ≥55 years to lower-intensity chemotherapy with or without blinatumomab to evaluate the impact of blinatumomab in older ALL.

CAR T-cell therapy in the frontline setting

Among patients with R/R ALL who receive CAR T-cell therapy, improved outcomes and reduced toxicities are observed among those with a lower disease burden [34, 35]. Therefore, positioning CAR T-cell therapy during consolidation/minimal disease should lead to reduced rates of CAR T-cell related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) while shortening treatment duration and potentially improving outcomes. This approach is being investigated in newly diagnosed patients with high-risk features and in older patients as a chemotherapy-sparing approach (Table 2). Several ongoing phase 2 studies using CAR T-cell as consolidation have reported high MRD-negativity rates of nearly 100% by NGS and 1-year OS rates of 90–100% among newly diagnosed patients with high-risk features [36, 37]. No grade ≥2 CRS or any grade ICANS were reported with this approach [37]. One of these phase 2 trials (NCT06481241) includes maintenance treatment after CAR T-cell consolidation, while the others do not administer any further therapy post-CAR T. While longer follow-up is needed to evaluate the durability of these responses, we have incorporated CAR T-cell consolidation into our practice with obecabtagene autoleucel (obe-cel) or brexucabtagene autoleucel (brexu-cel) for patients with high-risk disease features at diagnosis and in any patient with persistent NGS MRD-positivity after receiving blinatumomab. Patients who remain NGS MRD-positive after CAR T-cell therapy and show minimal CAR T-cell expansion/persistence are recommended for alloSCT [38, 39].

Table 2.

Clinical trial results incorporating CAR T-cell therapy in patients with newly diagnosed B-cell ALL.

Clinical trial	NCT06481241 (n = 44)	MDACC (n = 10a)	NCT05707273 (n = 18)
CAR T-cell product	4-1BB anti-CD19	Brexucabtagene autoleucel	Anti-CD19 CAR T-cell
Patient population	Adults ≥18 years	Adults ≥18 years with high-risk genomicsb or MRD-positivity or R/R B-ALL	Adults ≥55 years in CR1 after any frontline therapy
Treatment Schema	Pediatric-inspired induction → consolidation→ CAR T-cell → maintenance	HCVAD or mini-HCVD-InO-blinatumomab x ≥ 1–2 cycles → CAR T-cell	One CAR T-cell infusion
Median age (range), years	36 (18–70)	35 (19–77)	64 (55–79)
MRD negative rate (%)	100 97 (NGS)	100 (NGS)	NA
CRS (%)	59% (Grade 1)	57% (Grade 1)	72% (Grade 1)
ICANS (%)	0	0	0
Median follow up (months)	10.6	7.1	14.5
Survival rate (time-point)	OS: 100% (1 yr) LFS: 98% (1 yr)	OS: 93% (6 months) EFS: 79% (6 months)	OS: 100% (1 yr) PFS: 90% (1 yr)
Allogeneic SCT—n. (%)	5 (11)	2 (14)	1 (6)

CAR chimeric antigen receptor, MRD measurable residual disease measured by multiparameter flow cytometry, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, SCT stem cell transplantation, NGS next-generation sequencing, R/R relapsed/refractory.

^aFour R/R patients also treated.

^bDefined as KMT2Ar, complex karyotype, low hypodiploidy/tetraploidy, CRLF2r, or TP53m.

Philadelphia chromosome-positive B-cell ALL

Blinatumomab in combination with potent TKIs has led to promising outcomes in Ph-positive ALL, sparing the need for intensive chemotherapy and alloSCT (Table 3). Multiple phase 2 studies demonstrated high complete molecular response (CMR; undetectable BCR::ABL1 transcripts) rates (>75–90%) and OS rates (80–90%) with the combination of blinatumomab and dasatinib or ponatinib. Differences between the trials included a sequential approach of dasatinib followed by blinatumomab (D-ALBA; SWOG) compared to concomitant ponatinib and blinatumomab from induction (MD Anderson). Rates of alloSCT were also different, 38% on the D-ALBA trial versus 3% with blinatumomab-ponatinib [40–44]. The phase 3 GIMEMA ALL2820 trial randomized patients to blinatumomab plus ponatinib (n = 158) or chemotherapy plus imatinib (n = 78) [45]. The blinatumomab-ponatinib regimen was associated with a higher CR rate (94% versus 79%; p = 0.001) and MRD-negativity rate after 2 cycles of therapy (70% versus 59%; p = 0.009) [45]. An equal number of patients in each arm (19%) proceeded to alloSCT. Patients with persistent MRD-positivity, refractory disease, or those with ABL1 kinase domain mutations could cross over to receive blinatumomab. After a median follow-up of 23.4 months, treatment with blinatumomab-ponatinib led to a significantly higher 18-month EFS rate of 90% (95% CI: 86–95) versus 74% (95% CI: 65–85) with chemotherapy (p = 0.0015). The 18-month OS rate was 94% (95% CI: 91–98) with blinatumomab-ponatinib, 77% [46–71] with chemotherapy-imatinib and 97% (95% CI: 90-100) among the 31 patients who crossed over to the blinatumomab-ponatinib arm (p = 0.00071) [45]. This is the first randomized trial to demonstrate an improvement in outcomes with blinatumomab-ponatinib over chemotherapy-imatinib, confirming the benefit of the blinatumomab-ponatinib pilot trial conducted at MD Anderson. A propensity score analysis comparing blinatumomab-ponatinib with Hyper-CVAD plus ponatinib demonstrated improved 3-year PFS and OS rates with blinatumomab-ponatinib over Hyper-CVAD plus ponatinib, with significantly fewer patients proceeding to alloSCT (3% versus 20%; p = 0.029), a shorter overall treatment duration (5 blinatumomab courses compared to ~2.5 total years of therapy) and omission of intensive chemotherapy [72–74].

Table 3.

Clinical trial results incorporating novel therapies in patients with newly diagnosed Philadelphia chromosome-positive B-cell ALL.

	Blinatumomab + Dasatinib		Blinatumomab + Ponatinib		Olverembatinib	CAR T-cell consolidation
Clinical trial	D-ALBA (n = 63)	SWOG 1318 (n = 24)	MDACC (n = 88)	GIMEMA ALL2820a (n = 158)	POLARIS-1b (n = 55)	(n = 35)
Treatment schema	Dasatinib (D1-84)→blinatumomab x 2–5 cycles + dasatinib	Dasatinib (D1-84) + prednisone (D1-28)→ blinatumomab x 3 cycles + dasatinib→ maintenance	Blinatumomab x 5 cycles + ponatinib	Ponatinib (D1-70)→ blinatumomab x 2-5 cycles + ponatinib	Olverembatinib + low-intensity chemotherapy x 6 cycles→ maintenance x 12 cycles	Olverembatinib + low-intensity chemotherapy x 2-3 cycles→ olverembatinib + VEN + pred x 1–2 cycles→ 4-1BB CAR T-cell→ maintenance
Median age, (range) years	54 (24–82)	73 (65–87)	50 (18–83)	57 (19–84)	43 (NA)	39 (20–60)
CR rate (%)	98	92	95	94	94	100
CMR rate (%)	93	75	83 (95% by NGS)	80	57 (MR4)	100 (post CAR T-cell)
Median follow-up	53 months	5.6 years	32 months	23 months	NA	11 months
Survival rate (time-point)	OS: 81% (4 yr) EFS: 75% (4 yr)	OS: 63% (5 yr) DFS: 64% (5 yr)	OS: 89% (3 yr) EFS: 79% (3 yr)	OS: 94% (18 months) EFS: 90% (18 months)	NA	OS: 100 (1 yr) LFS: 100 (1 yr)
Allogeneic SCT—n. (%)	30 (48)	1 (4)	2 (3)	30 (19)	5 (9)	3 (9)
Relapse—n. (%)	9 (14)	8 (33)	11 (13)	9 (6)	3 (5)	0
CNS relapse—n. (%)	4 (6)	2 (8)	5 (6)	1 (0.6)	NA	0

CAR chimeric antigen receptor, CR complete response, CMR complete molecular response, SCT stem cell transplantation, CNS central nervous system, D days, OS overall survival, EFS event-free survival, NGS next generation sequencing, MR4 BCR::ABL1 < 0.01% by PCR, LFS leukemia-free survival.

^aResults for the 158 patients randomized to blinatumomab plus ponatinib.

^bResults for the 55 patients enrolled in part A of the phase 3 trial receiving olverembatinib.

Despite these excellent outcomes with blinatumomab, there remains a subset of higher-risk patients in which intensification of consolidation may be required. In the phase 2 blinatumomab-ponatinib study, baseline WBC ≥ 70 × 10⁹/L was associated with a significantly increased rate of relapse on multivariate analysis [75]. After a median follow-up of 32 months, a significantly higher 3-year cumulative incidence of relapse (CIR) was observed with WBC ≥ 70 × 10⁹/L compared to WBC < 70 × 10⁹/L (31% versus 6.7%; p = 0.005) [42]. Seven (64%) of the 11 relapses were in patients with WBC ≥ 70 × 10⁹/L and five (45%) were CNS relapses. Due to the increased relapse rate in this subgroup, the trial has been amended to add two courses of high-dose methotrexate and cytarabine consolidation (50% of doses; blinatumomab starts Day 4 ×14 days with each course). We also pursue CAR T-cell consolidation for these patients. Patients with the IKZF1^plus genotype are another high-risk subgroup of interest. The DFS rate was significantly worse among these patients when treated with blinatumomab-dasatinib compared to those without IKZF1^plus (46% versus 83%) [41]. Of interest, with blinatumomab-ponatinib, the IKZF1^plus genotype was not associated with an increased risk of relapse [75]. No difference in the rates of CIR (16% versus 20%; p = 0.6) or death without relapse (9% versus 4%; p = 0.6) was noted in patients with or without IKZF1^plus [41, 42]. The combination of blinatumomab and ponatinib may overcome the poor prognosis of IKZF1^plus in patients with Ph-positive ALL, although more robust prospective analyses are needed. Our current approach in Ph-positive ALL is the blinatumomab-ponatinib regimen for all frontline patients, with chemotherapy intensification for patients with WBC ≥ 70 ×10⁹/L. All patients receive 15 intrathecals (ITs) with cytarabine alternating with methotrexate (usually Days 2, 14 and 28 of each of the blinatumomab courses). Of interest, about 20–25% of patients on blinatumomab-ponatinib become NGS MRD-negative but have persistent low BCR::ABL1 transcript levels [76]. That molecular signal is not emanating from residual lymphoblasts, but perhaps from myeloid cells. Such patients do not relapse with Ph-positive ALL and are not offered alloSCT. However, they continue with ponatinib beyond 5 years of NGS-MRD negative/BCR::ABL1 positive status. This is in contrast to patients who are negative by both tests for 5+ years, in whom we may consider holding TKI therapy and observing closely (as is our practice in chronic myeloid leukemia after 5+ years of BCR::ABL1 transcripts negativity status at our institution) [77].

Ponatinib is our TKI of choice as it has demonstrated superiority over imatinib in the phase 3 PhALLCON trial and dasatinib in retrospective analyses [78, 79]. Olverembatinib, a novel third-generation BCR::ABL1 TKI, is currently being investigated in the phase 3 POLARIS-1 trial compared to dealer-choice TKI (including ponatinib), combined with low-intensity chemotherapy, in newly diagnosed patients, with a primary endpoint of MR4 (BCR::ABL1 transcripts ≤0.01% by PCR) after induction Course 3. The MRD-negative CR rate at the end of induction from the 55 patients treated in the lead-in portion with olverembatinib was 53% [80]; the results from the randomized trial are highly anticipated.

The pursuit of CAR T-cell therapy as consolidation for patients with Ph+ ALL is being explored, however at this time remains investigational. (Table 3). Early results from a phase 2 study incorporating a single CAR T-cell infusion into consolidation, followed by TKI maintenance has demonstrated a 1-year OS and LFS rate of 100% after a median follow-up of 11 months [81]. We are currently exploring adding CAR T-cell infusions in high-risk patients (WBC > 70 ×10⁹/L) on blinatumomab-ponatinib (Fig. 1B). This might further reduce the occurrence of systemic and CNS relapses.

An ongoing study in Ph+ ALL is the phase III EA181 trial (NCT04530565), which randomizes adults with newly diagnosed Ph+ ALL to induction with steroids plus TKI in combination with chemotherapy versus steroids plus TKI in combination with blinatumomab. These data will be important to help confirm the role of frontline immunotherapy-based regimens in frontline Ph+ ALL.

MRD monitoring and implications

The BLAST trial led to FDA approval of blinatumomab for patients with MRD-positivity (≥10⁻³). However, prior to the E1910 trial results, the impact of blinatumomab in patients with a lower level of disease burden was unknown [82]. As a result, a phase 2 study administering blinatumomab (up to 5 courses) for MRD-positivity at a lower threshold (≥10⁻⁴) was initiated at our institution. The long-term follow up has demonstrated a 5-year OS rate of 60% (95% CI: 42–73) and relapse-free survival (RFS) rate of 49% (95% CI: 32–64) [83, 84]. A landmark analysis of patients treated in CR1 demonstrated a 5-year OS rate of 67% versus 57%, respectively, for those who proceeded to alloSCT or did not [84]. Evaluation with NGS can further discriminate between patients who may or may not benefit from alloSCT. Among patients who achieve NGS MRD-negativity with blinatumomab, excellent long-term outcomes including 2-year RFS and OS rates of 71% and 100%, respectively, have been reported. Patients who do not achieve NGS MRD-negativity with blinatumomab can benefit from alloSCT with a landmark analysis demonstrating a 2-year RFS rate of 63% with alloSCT versus 10% (p = 0.02) without alloSCT [85]. InO has also been studied in 37 patients with MRD-positivity ≥10⁻⁴ in a phase 2 clinical trial (including 65% of patients who had received prior blinatumomab and 11% prior CAR T-cell) [86, 87]. Overall, 25 patients (68%) achieved MRD-negativity by MFC, NGS, or PCR. The median OS was 40 months after a median follow-up of 39 months. The median OS for patients treated in CR1 was 61 months compared to 14 months for patients treated in CR2 or later (p = 0.06). The 3-year OS rate for patients who achieved MRD-negativity after InO and proceeded to alloSCT was 71% compared to 56% for those who did not proceed to alloSCT (p = 0.6); the 3-year EFS rate was 57% versus 44% (p = 0.43) [86, 87].

Overall, these results indicate that blinatumomab, and possibly InO, may allow a subset of patients treated in CR1 who achieve deep NGS MRD-negativity to defer alloSCT. Of note, CAR T-cell therapy used in patients with R/R who are infused at a time of <5% marrow blasts (i.e. post bridging therapy and in second CR/minimal disease burden) have also benefited, with 1-year OS rate of 72% [88]. In our current trials, we rely on NGS (sensitivity 10⁻⁶) to identify the subset of high-risk patients who may pursue consolidation with CAR T-cell rather than alloSCT. Other than those with KMT2Ar, high-risk patients with Ph-negative ALL who achieve NGS MRD-negativity after Cycle 1 of induction have the best outcomes and may not benefit from alloSCT. Alternatively, CAR T-cell is being evaluated in this setting [76, 89]. However, regardless of NGS-MRD status, we continue to refer patients with KMT2Ar for consolidation with alloSCT in CR1.

T-cell ALL

T-cell ALL represents ~10–25% of ALL diagnoses, but unlike B-cell ALL, few novel agents have been recently developed for this entity. The randomized phase 3 AALL0434 trial in pediatric T-cell ALL demonstrated that the addition of nelarabine improved DFS among patients treated with the high-dose methotrexate backbone, whereas no significant benefit was seen in those receiving the Capizzi-style methotrexate regimen [90]. The Hyper-CVAD regimen has been modified to include nelarabine, peg-asparaginase, and most recently venetoclax. Forty-six patients have been treated with this entire schema. After a median follow-up of 24 months, the 2-year PFS and OS rates were 88%, compared to a 2-year PFS rate of 64% (p = 0.03) and 2-year OS rate of 74% (p = 0.16) with the original treatment schema [91]. Of note, studies on mini-CVD plus venetoclax and navitoclax have shown encouraging efficacy in both B-cell and T-cell ALL [46, 47]. These findings support the biological vulnerability of T-cell ALL to BCL-2 family inhibition and suggest that dual BCL-2/BCL-XL targeting may enhance depth of response.

Although no product is currently commercially available, anti-CD7 CAR T-cell products are actively being investigated in T-cell ALL, utilizing various approaches to reduce fratricide (Table 4A) [48–50]. Phase 1 results from two ongoing clinical trials evaluating allogeneic base-edited (BE-CAR7) and second-generation 41BB (WU-CART-007) anti-CD7 CAR T-cells showed response rates of ≥73% and high MRD-negativity rates of 70-73% among patients with R/R T-cell ALL/LBL [50, 51]. Grade ≥ 3 CRS occurred in approximately 20% of patients, typically among patients with high burden of disease; only grade 1 ICANS was reported [50, 51]. Survival data are encouraging, particularly for those who are able to proceed to alloSCT. The phase 2 portions of these studies are highly anticipated. A pooled analysis of ongoing phase 1/2 studies of the autologous anti-CD7 CAR CTD402 has demonstrated a median DOR of 9.7 months (95% CI: 5-NR) after a follow up of 21.2 months with low rates of grade ≥3 CRS (12%) and no ICANS [52]. Additional toxicity with anti-CD7 CAR products include prolonged cytopenias and late-onset infections, particularly with donor-derived products and in those who are unable to proceed to alloSCT [53, 54]. Continued research is ongoing in this setting where few treatment options exist.

Table 4.

A Ongoing clinical trials with CAR T-cell therapy in patients with relapsed and/or refractory T-cell ALL. B Ongoing clinical trials with novel bispecific T-cell engager products in relapsed and/or refractory B-cell ALL.

A
Clinical trial	BE-CAR7 (n = 11) [Chiesa]	CTD402 (n = 41) [Lu]	WU-CART-007 (n = 26) [Ghobadi]
CAR T-cell product	Allogeneic base-edited anti-CD7 CAR (BE-CAR7)	Autologous anti-CD7 CAR	Allogeneic anti-CD7 CAR
Patient population	Patients (≥6 months) with R/R T-cell ALLa	Pediatric and adult patients with R/R T-cell ALL/LBL	Patients ≥12 years with R/R T-ALL/LBL
Median age (range), years	12 (5.9–38)	27 (10–56)	30 (14–69)
CR/CRi rate (%)	100	64	73b
MRD negative rate (%)	73	92	70
Grade ≥3 CRS (%)	18	12	19
ICANS (%)	27% (Grade 1)	0	8% (Grade 1)
Median follow up (months)	NA	21.2 months	NA
Survival	OS: 73%DFS: 64%	Median DOR: 9.7 months (5.0-NR)	Median DOR: NR (0.5-NE)
Allogeneic SCT—n. (%)	9 (82)	12 (31)	8 (31)

B
Clinical trial	SubQ Blina (n = 88) [Jabbour]	MK-1045 (n = 75) [Wang]	AZD0486 (n = 42) [Aldoss]
Patient population	Adults ≥18 years with R/R B-cell ALL	Adults ≥18 years with R/R B-cell ALL	Patients ≥16 years with R/R B-cell ALL
Prior blinatumomab Prior CAR T-cell Prior alloSCT	17 (22) 14 (18) 23 (29)	7 (9) 5 (7) 11 (15)	18 (43)d 17 (40)d NA
Median age, (range) years	49 (19–78)	46 (18–73)	50 (17–77)
CR/CRi rate (%)	77	83c	82e
MRD negative rate (%)	88	90c	100e
Grade ≥3 CRS rate (%)	17% (250/500 mcg dose) 23% (500/1000 mcg dose)	3	9 (Grade ≥2)
Median follow up	14 months	16 months	6.2 months
Median DOR	18.4 months	11.3 months	NR
OS rate (time-point)	69% (1 yr)	NA	NA
Allogeneic SCT—n. (%)	32 (36)	NA	8 (19)

CAR chimeric antigen receptor, CR complete response, CRi CR with incomplete blood count recovery, MRD measurable residual disease measured by multiparameter flow cytometry, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, SCT stem cell transplantation, OS overall survival, DFS disease-free survival, DOR duration of response, NR not reached, R/R relapsed/refractory.

^aClinical trial enrolled patients ≥6 months-16 years of age, adults ≥18 years who received product via compassionate use program also included in analysis.

^bCR/CRi and DOR results for n = 11 evaluable patients who received RP2D.

^cAmong the 24 patients receiving target dose ≥60 mg.

^dPatients may have received both blinatumomab and/or CAR T-cell.

^eAmong the 17 patients receiving target dose of 15 mg.

Relapsed/refractory ALL

Outcomes in adult R/R ALL are poor with traditional intensive chemotherapy, with or without subsequent alloSCT. With chemotherapy, the CR rates in salvage 1 are 40%, and the 3-year OS rates <10–12% [1, 2, 55]. Single agent blinatumomab and InO, approved for the treatment of R/R ALL, result in CR rates of 50–60%, but the median OS is only 7–8 months and the 2-year OS rate 20% or less [56, 57]. CAR T-cell therapies in adult ALL produce high CR rate and 2-year OS rates of 40% [34, 58, 88]. As a result, treatment in the adult R/R ALL setting relies on combination and CAR T-cell therapy. The “dose-dense” mini-Hyper-CVD-InO-blinatumomab schema combines mini-Hyper-CVD-InO with blinatumomab in each treatment cycle for a total of 6 cycles [59]. An overall response rate (ORR) of 100% (CR: 79%) and NGS MRD-negativity rate of 95% was reported among 25 patients treated [60]. After a median follow-up of 25 months, the estimated 2-year EFS rate was 69% and 2-year OS rate was 77%. The 2-year OS rate for patients who proceeded to alloSCT, CAR T-cell, or no further therapy was 100%, 89%, and 52%, respectively (p = 0.18) [60]. Another analysis of patient outcomes in first salvage indicated that patients who achieved an MRD-negative CR by MFC after induction and had a long first remission (≥12 months) did not benefit from alloSCT consolidation [61]. The 4-year RFS rate was 62% for those who were transplanted versus 59% for those who were not (p = 0.77), and the 4-year OS rates were 74% and 67%, respectively (p = 0.84). The benefit of alloSCT was observed for both RFS and OS among patients with a short first remission (<12 months) and/or MRD-positivity by MFC after induction [61]. A recent study combining InO with venetoclax in R/R ALL reported a CR rate of 95%, NGS-MRD negative rate of 74% and a median DFS of 36 months (2-year DFS and OS rates about 60%) [62]. At MD Anderson, to treat R/R ALL today, we utilize the dose-dense mini-Hyper-CVD-InO-blinatumomab regimen followed by CAR T-cell consolidation (Fig. 1D). Obe-cel is a recently approved CAR T product for R/R ALL and has demonstrated similar efficacy to brexu-cel with improved tolerability [63, 88]. Obe-cel led to a CR/CRi rate of 78%, 2-year EFS rate of 43% and 2-year OS rate of 46% after a median follow-up of 33 months among 127 patients with R/R ALL treated in the FELIX trial [88]. Superior outcomes were observed among patients who achieved NGS MRD-negativity (<10⁻⁶) and in those with ongoing CAR T-cell persistence measured 3 months post-infusion with median EFS and OS not reached even without consolidative alloSCT [38, 64]. Among high-risk patients treated with brexu-cel, a real-world analysis demonstrated inferior response and survival outcomes among patients with KMT2A-rearranged ALL compared to standard-risk patients, demonstrating the need for novel therapies in this subset [65]. Consideration for alloSCT is multifactorial, based upon first remission duration, MRD response, as well as CAR T-cell expansion and persistence [38, 39].

Novel formulations such as subcutaneous blinatumomab and CD19xCD3 BiTEs are under development for the treatment of R/R ALL (Table 4B). A phase 1/2 multicenter study reported the safety and efficacy of subcutaneous blinatumomab with a CR/CRh rate of 77%, MRD-negativity rate of 88%, and estimated 12-month OS rate of 69% among 88 patients treated [66, 67]. Two ongoing phase 1/2 studies investigating novel BiTEs, MK-1045 and AZD0486 (surovatamig), have demonstrated promising results (Table 4B) [68, 69]. Continued evaluation of these new therapies and confirmation of early findings are needed.

Patients with CNS relapse have historically been treated with CNS-directed intensive or intrathecal chemotherapy, and/or cranial radiation [70]. Currently, CAR T-cells are being investigated in this space. The outcomes of 42 patients treated with tisagenlecleucel reported an overall CNS remission rate of 100% [71]. The 2-year EFS rate was 90% (95% CI: 81–100). Of the 14 patients with >4 years of follow-up, the 4-year EFS rate was 65% (95% CI: 42–100) and 4-year OS rate was 93% (95% CI: 80–100). Grade ≥3 CRS was only reported in 1 patient and four patients (9%) experienced grade 3 neurotoxicity [71].

Conclusions

Treatment of adults with ALL has progressed from reliance on combination cytotoxic chemotherapy to novel, targeted therapies combined with minimal or no chemotherapy. This modernization of treatment has resulted in improved tolerability and outcomes in patients with both Ph-negative and Ph-positive B-cell ALL. Optimal treatment strategies are still needed for high-risk patients such as those with KMT2A-rearranged ALL, TP53-mutated ALL, ALL with complex karyotype, ETP-ALL, and older patients (≥70 years). Future progress through incorporation of CAR T-cell therapy into the frontline setting and integration of novel therapies into standard treatment backbones will hopefully continue to advance the outcomes in ALL.

Author contributions

EJ and HK were both responsible for the conceptualization, writing the original draft of the manuscript, providing edits and approving the final version.

Competing interests

The authors received research grants from Adaptive Biotechnologies, Ascentage, Abbvie, Takeda, Pfizer, Novartis, and Amgen pharmaceuticals. This work was supported by the MD Anderson Cancer Center Support Grant CA016672 and the “Charif Souki Cancer Research Fund”.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41408-026-01566-z.