Treatment of Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Free

Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer of immature lymphoid precursor cells that newly afflicts ∼6,500 individuals per year in the USA, approximately half children and half adults. ALL is the most common cancer in children where the age-specific incidence is highest. Fortunately, the vast majority of pediatric patients are cured, the result of decades of successful, international collaboration which led to the development of highly effective multi-agent chemotherapy regimens [1, 2]. In adults, however, outcomes are markedly inferior with risk of death from disease or the consequences of treatment, steadily increasing with each decade (Table 1) [3‒5].

ALL in adults is almost never a favorable, chemotherapy-sensitive subtype (such as hyperdiploid or ETV6::RUNX1-rearranged) and likely to be a chemotherapy-resistant subtype such as Philadelphia chromosome-positive, Philadelphia chromosome-like, TP53-mutated/hypodiploid, or KMT2A/MLL-rearranged, leading to high rates of treatment failure [6‒10]. ALL in older adults is also more commonly treatment-related or evolves from TP53 clonal hematopoiesis [11, 12].

Historically, there was little ability to effectively address high-risk ALL subtypes in adults, particularly older adults who do not tolerate chemotherapy intensification and myeloablative allogeneic hematopoietic stem cell transplant (HSCT) approaches. This led to a certain degree of therapeutic nihilism resulting in many patients over the age of 60 or 70 years receiving none or minimal treatment [13]. Now, the development of multiple effective, well-tolerated novel therapeutic agents is changing the landscape of ALL with particular implications for older adults where durable remissions, and even cure, may be more commonly achieved while preserving quality of life.

The definition of an older adult is imprecise but generally refers to an individual over the age of ∼50–60 years who is not eligible for an intensive, pediatric-inspired chemotherapy regimen which have been associated with high rates of cure [14‒16]. In this review, we will discuss data related to trials of novel agents focused on treating older patients with newly diagnosed Philadelphia chromosome-negative (Ph–) ALL, recognizing that some younger patients with comorbidities or significant obesity may be better served with approaches tailored to older adults while some very fit, normal weight patients in their 50s may be treated with pediatric-inspired regimens [17].

For an older adult with Ph– ALL, the first task of treatment is to safely bridge a patient from diagnosis to complete remission (CR). Early treatment resistance among adult patients with ALL is a major concern with chemotherapy-treated patients occasionally having overtly refractory (∼5 to 10%) disease and commonly (∼50%) having persistent measurable residual disease (MRD) after induction with conventional agents (Table 1) [16]. Disease resistance is related primarily to the frequency of genetically high-risk subtypes including Philadelphia chromosome-like ALL, ALL with KMT2A/MLL rearrangement, and hypodiploid/TP53-mutated ALL (the latter two subtypes often therapy-related) and the rarity of favorable chemotherapy-sensitive subtypes including hyperdiploid and ETV6-RUNX1 ALL [6‒12].

Traditional approaches to improving outcomes in ALL have focused on chemotherapy intensification, a tactic with significant success in children and young adults but with limited success in older adults [1]. Historically, the primary cause of early treatment failure in Ph– ALL was death during induction. Even among patients sufficiently fit for clinical trial participation (an already selected group), early mortality has consistently been recorded in 10–20% of patients [16, 18‒24]. For instance, the Cancer and Leukemia Group B (CALGB) 8811 trial implemented dose reductions in cyclophosphamide, daunorubicin, and prednisone (POMP) for patients >60 years due to high induction mortality, primarily related to infection [24]. Even with dose reductions, however, death before remission assessment was markedly higher in patients >60 years (50%) compared to younger patients (<30 years – 1%, 30–59 years – 8%). The more recent French Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL)-2005 trial continued to show induction deaths rising sharply by age from 1.1% to 7.1% to 18.3% among patients aged 18–34, 35–54, and 55–59 years, respectively [16]. In the successor GRAALL-2014 trial, dose reductions during induction and delayed intensification were implemented for patients ≥45 years which decreased the rate of death during induction (11% to 3%, p < 0.001), thereby improving the CR rate (86% to 92%, p = 0.045) and overall survival (OS), but at the cost of increased relapse (27% to 39%, p = 0.02) [25]. Given the frequency of chemotherapy-resistance and toxicity in adult ALL, novel agents including blinatumomab, inotuzumab, and venetoclax have been rapidly introduced into regimens for older adults with the dual goal of improving efficacy and reducing morbidity by facilitating the reduction or omission of conventional chemotherapy (Tables 2, 3).

Blinatumomab, a bi-specific T-cell engager, was first studied in the upfront treatment of older patients with newly diagnosed Ph– B-ALL in the US Southwest Oncology Group (SWOG) 1318 trial (Table 2) [30]. Among 29 treated patients ≥65 years, 19 (66%) achieved CR/CR with incomplete hematologic recovery (CRi), with MRD negativity (<10⁻⁴ by multi-parameter flow cytometry) achieved in 92% (12/13) of assessed patients. While blinatumomab induction was safe (1 early death, 1 early discontinuation for adverse event), the relatively low CR rate highlights the limitations of blinatumomab in the setting of high tumor burden [34‒37]. Blinatumomab may be better integrated into ALL induction by administering it concurrently with, or subsequent to, reduced doses of conventional chemotherapy to aide in cytoreduction, a strategy employed by the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) BOLD, HOVON (Stichting Hemato-Oncologie voor Volwassenen Nederland)-146, and pharmaceutical industry-sponsored Golden Gate studies (Table 2) [27, 32, 38‒40]. The Golden Gate study (NCT04994717) is a phase 3, international study randomizing adults ≥55 years to receive low-intensity chemotherapy with or without 7 cycles of blinatumomab alternating with chemotherapy (2 blinatumomab cycles during induction, 2 blinatumomab cycles during consolidation, and 3 blinatumomab cycles during maintenance); blinatumomab cycles during induction and consolidation are administered concurrently with low-intensity chemotherapy [27]. An acceptable safety profile was demonstrated in the safety run-in with final results awaited. Subcutaneous blinatumomab is under development and the superior pharmacokinetics (higher drug exposure) may enhance the performance of blinatumomab during remission induction [41].

Inotuzumab, an anti-CD22-humanized IgG4 antibody linked to calicheamicin, is being used by multiple groups in the induction setting given its ability to effectively treat ALL regardless of disease burden (Tables 2, 3) [42]. Initially, several studies combined inotuzumab with chemotherapy at significantly reduced doses (European Working Group for Adult Acute Lymphoblastic Leukemia [EWALL]-InO, MD Anderson Cancer Center [MDACC] inotuzumab plus hyperfractionated cyclophosphamide, vincristine, and dexamethasone [HCVD]) [26, 29]. Recognizing that administering chemotherapy currently with inotuzumab adds toxicity and may have limited incremental benefit, other studies have approached induction with single agent inotuzumab (GMALL INITIAL-1, US Alliance A041703) [28, 31]. In general, these trials have achieved CR rates in excess of 90% with the majority being MRD-negative (at 10⁻⁴), with low early mortality and only rare occurrences of significant liver toxicity (including sinusoidal obstructive syndrome [SOS]).

The ongoing Alliance A042001 trial is a phase 2 trial randomizing older adults (≥50 years) to a conventional chemotherapy induction (age-adjusted hyperfractionated cyclophosphamide, vincristine, doxorubicin/Adriamycin^® and dexamethasone [HCVAD]) or an inotuzumab-based induction with attenuated chemotherapy (inotuzumab plus HCVD) with goal of showing in a randomized fashion the benefit of adding a novel agent to the early phase of treatment (primary endpoint = modified event-free survival [EFS] with the event definition inclusive of failure to achieve an MRD-negative CR) (Table 2).

Preclinical studies show sensitivity of lymphoblasts to selective BCL2 inhibition (venetoclax), as well as the ability of BCL2 inhibitors to potentiate chemotherapy (Table 3) [43‒50]. This fact has inspired clinical studies integrating venetoclax with dose-reduced chemotherapy for older adults, with safety demonstrated in the first-line and relapsed setting, and efficacy appearing to be particularly encouraging in untreated patients (Table 2) [33, 51, 52]. Among 30 newly diagnosed patients ≥55 years (median age 68 years, 40% ≥70 years) treated with venetoclax plus HCVD, an MRD-negative CR was achieved in 83% (25/30) of patients with 1 patient experiencing early death and 1 refractory patient [51]. Notably, 9 patients had TP53-mutated disease (with hypodiploid or complex karyotype) and 8 patients had received prior chemotherapy for multiple myeloma (6) or other cancers. Most patients achieved MRD-negative CR (at 10⁻⁴) after a single cycle and venetoclax did not negatively impact time to count recovery (median time to cycle 2 was 34 days). This regimen does not require expression of lineage-specific markers and is thus applicable to patients with T-cell ALL and KMT2A/MLL-rearranged acute leukemia. Future approaches to induction may involve combinations of novel agents such as inotuzumab and venetoclax [53, 54], but caution must be exercised to ensure that any intensification of therapy does not increase toxicity and compromise the initial goal of consistently and safely achieving CR.

After achievement of CR, the therapeutic goal is to maintain and deepen an achieved remission without incurring therapy-related toxicity. Various studies have taken different approaches combining novel agents with or without chemotherapy (Tables 2, 3).

Inotuzumab has typically been concentrated in induction and early consolidation given efficacy of this drug in the setting of high tumor burden and concerns regarding risk of cumulative toxicity in patients receiving more than two or three cycles (Table 3) [26, 28, 29, 31, 42]. The cumulative dose of inotuzumab varies by protocol: MDACC inotuzumab plus HCVD (initially 3.7–5.7 mg/m², amended from patient 50 to a lower fractionated dose of 2.7 mg/m²), EWALL-InO (2.8 mg/m²), Alliance 041703 (3.6 mg/m²), GMALL INITIAL-1 (4.8 mg/m²) (Table 2). Investigators at MDACC reduced the dose of inotuzumab early in the development of their regimen due to observation of cases of SOS [26]. The investigators also reduced the amount of conventional chemotherapy delivered due to the high incidence of therapy-related mortality in patients ≥70 years secondary to infections during later chemotherapy cycles, as well as multiple cases of therapy-related myeloid neoplasm. Notably, the regimen has continued to evolve with complete omission of chemotherapy in patients ≥70 years and simultaneous administration of inotuzumab and blinatumomab [55]. Interestingly, an increased incidence of infection has been seen in pediatric and young adult patients treated with inotuzumab in combination with frontline chemotherapy regimens, suggesting that post-inotuzumab infections may at least in part be related to sustained impact of the drug itself on the immune system [56].

Blinatumomab has become the favored consolidation approach given efficacy in the setting of lower tumor burden and the results of the Eastern Cooperative Oncology Group-American College of Radiation Imaging Network (ECOG-ACRIN) 1910 trial [35‒37, 57, 58]. The ECOG-ACRIN 1910 trial was a phase 3 trial that randomized adult patients (aged 30–70 years) in an MRD-negative (<10⁻⁴ by flow cytometry) CR after chemotherapy to receive or not receive 4 courses of blinatumomab in addition to conventional consolidation chemotherapy [37]. The ECOG 1910 study initially enrolled 488 patients among whom 19 (4%) died from toxicity during induction, 74 (15%) were refractory, and 395 (81%) achieved a CR or CRi. Of the 395 patients who achieved CR/CRi, 109 did not reach next randomization point due to death, disease relapse, adverse events, or withdrawal during the intensification phase of chemotherapy. Among the 286 patients who did reach the randomization step, 224 were MRD-negative and 62 were MRD-positive. Among randomized MRD-negative patients (224 [46%] of the 488 who originally enrolled), there was a significant improvement in OS (85% vs. 65%, HR, 0.41, p = 0.002) and relapse-free survival (80% vs. 64%, HR 0.53) which led to US Food and Drug Administration (FDA) approval in June 2024 of blinatumomab in consolidation in combination with a chemotherapy regimen for CD19+ Ph– ALL, regardless of age. The benefit of blinatumomab was more convincing in younger patients. While not powered for subgroup analysis, there was no benefit demonstrated in older patients – the reasons are not clear but may relate to the late introduction of blinatumomab or the quite intensive chemotherapy backbone. Interestingly, the MDACC phase 2 inotuzumab plus HCVD which added blinatumomab consolidation after the initial 50 patients enrolled has also not shown an improvement in outcome in later blinatumomab cohorts compared to earlier pre-blinatumomab cohorts [26]. Almost all ongoing and planned trials for adult ALL, including older adults, will incorporate blinatumomab during post-remission treatment with further study required to understand ideal timing, duration of treatment (number of cycles, continuous or intermittent), and formulation (intravenous vs. subcutaneous blinatumomab) [41]. Of note, an unplanned landmark analysis of the ECOG 1910 study suggested superior outcomes among patients who received all 4 planned blinatumomab cycles compared to those who received 1–2 cycles [59].

An intriguing question in the era of novel agents is whether chemotherapy can be completely abandoned for older adults. Indeed, now multiple studies – SWOG 1318, Alliance 041703, and current iterations of the MDACC inotuzumab plus HCVD protocol – are treating older adults with only novel agents (Table 3). The SWOG 1318 study treated 29 patients (median age 75 years) with blinatumomab induction followed by blinatumomab consolidation, achieving a 3-year DFS of 37% [30]. The Alliance 041703 study treated 33 patients (median age 71 years) with inotuzumab induction followed by blinatumomab consolidation achieving a 1-year EFS of 75% with updated follow-up soon expected [31]. Thus, it is clear that some patients may achieve durable remissions without any chemotherapy. Which patients may benefit from receiving a combination of one or more novel agents alternating or combined with courses of conventional chemotherapy is not known. Conventional chemotherapy may have the specific advantage of penetrating the central nervous system (CNS) as well as preventing disease relapse via clones with resistance to CD19- and CD22-directed therapy. Venetoclax may be combined with chemotherapy in the post-remission setting, perhaps enhancing efficacy [33, 51]. Randomized studies are needed to understand merits of different approaches, with attention to both systemic and CNS disease control as well as early and late toxicity.

In childhood ALL, incorporation of a prolonged maintenance phase based on continuous exposure to the anti-metabolites mercaptopurine and methotrexate (and variable incorporation of vincristine and corticosteroid pulses) is critical to the consistent achievement of cure [60]. Shortening or incomplete adherence to maintenance therapy in the pediatric and AYA populations is associated with inferior outcomes [61, 62].

Building on this experience, virtually all chemotherapy regimens for Ph– ALL in adults incorporate a maintenance phase, yet there are modest data to justify this approach. In a single-institution retrospective study of 37 adults ≥60 years with ALL treated as per ECOG 2993/UKALL XII regimen, having received versus not received maintenance therapy had a positive impact on EFS and OS [63].

Modern regimens for older adults that include novel agents have taken multiple approaches to maintenance ranging from adjustment of conventional chemotherapy doses and durations, integration of the novel agents, to omission of this phase of therapy altogether. In SWOG 1318, a chemotherapy-free regimen of blinatumomab induction followed by blinatumomab consolidation was followed by a planned 18 months of traditional mercaptopurine, vincristine, methotrexate prednisone (POMP) maintenance. However, the median number of POMP cycles received was only 4 (range 1–18), highlighting issues with patient attrition [30]. In contrast, Alliance 041703 which tested a chemotherapy-free regimen of inotuzumab induction followed by blinatumomab consolidation eschewed maintenance altogether [31]. By comparison, in the MDACC phase 2 study of inotuzumab plus HCVD +/− blinatumomab study, maintenance was initially 3 years of POMP, later amended to 12 cycles with every fourth POMP cycle replaced by blinatumomab [26]. The amendment was part of revisions undertaken to address the significant issue of death in remission seen in this study (44% of study population overall), including 8 who succumbed to infection and 9 to secondary myeloid neoplasms. The GMALL Bold trial studying dose-reduced chemotherapy sequenced with blinatumomab reduced vincristine and prednisone to an every 12-week schedule with duration of maintenance limited to 1 year [32]. In the recently reported phase 1 study of venetoclax and HCVD, venetoclax was added to each cycle of POMP maintenance, but the majority of patients did not receive this component of therapy given the high rate of HSCT in CR1 [33]. Thus, overall, in older adults, data to guide the optimal approach to maintenance, including agents and duration, are lacking.

Incorporating novel agents into frontline therapy is moving the needle for older adults with newly diagnosed Ph– ALL. However, disease relapse remains a challenge particularly for patients with high-risk genetics prompting consideration of cellular therapy-based consolidation strategies.

Reduced intensity conditioning (RIC) can put HSCT within reach of fit, older adult patients with ALL. Retrospective studies of relatively younger ALL cohorts (median age 40s–50s) reported that conditioning intensity does not affect OS or leukemia-free survival (LFS) [64, 65]. Another retrospective study focusing on adults ≥55 years with B-ALL undergoing RIC HSCT (most CR1) found a 3-year 25% cumulative incidence of non-relapse mortality (NRM) and 47% cumulative incidence of relapse with the most frequent cause of death being relapsed leukemia [66]. Lower performance status was associated with NRM highlighting the importance of patient selection [65, 66]. The ability to apply this historical data is limited for two reasons. First, in the era of novel agents and improved assessment of MRD, patients may be entering RIC transplant with better disease control (MRD-negative CR), which may reduce relapse risk. Second, significant improvements in the prevention and treatment of graft-versus-host disease may decrease NRM. More study on the efficacy and tolerability of RIC HSCT in older adults with ALL is needed, as well as a better understanding of which patients stand to benefit from this therapeutic escalation after treatment with novel agent-based regimens.

The historically high rate of NRM in older adults with ALL undergoing HSCT has fueled interest in using CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T) as definitive consolidation. Brexucabtagene autoleucel (brexu-cel) was the first CD19-targeted CAR-T approved for the treatment of relapsed and refractory (R/R) B-ALL in adults based on the ZUMA-3 trial which notably included only 8 patients older than 65 years [67]. A recent retrospective analysis of 73 R/R B-ALL patients ≥60 years from a brexu-cel consortium database found similar rates of MRD-negative CR (59% versus 66%) as well as grade 3–4 cytokine release syndrome (CRS) and grade 3–4 immune effector cell-associated neurotoxicity syndrome (ICANS) compared to patients <60 years. There was also no statistically significant difference in OS among patients <60, 60–69, and ≥70 years, but patients ≥70 years had significantly lower 12-month progression-free survival (PFS, 38%) compared to patients 60–69 (64%) and <60 (57%) years [68]. Recently, obecabtagene autoleucel (obe-cel) was approved for adults with R/R B-ALL demonstrating high rates of MRD-negative remissions and durable responses in the ALLCAR19 and FELIX studies [69, 70]. The remarkably low rates of grade 3–4 CRS and ICANS (2.4% and 7.1%, respectively) make it a particularly attractive product for treating older adults. In the FELIX trial, as in previous trials, a correlation between burden of disease and response was demonstrated, with the best EFS and OS in patients with <5% bone marrow blasts prior to lymphodepletion [70]. CAR-T therapy is now being explored in the frontline with the rationale that employing CAR-T early in disease course when there is superior fitness of both patient and T cells as well as more sensitive, low volume disease will converge to generate durable remissions [71]. A recent, single-center pilot study treated patients age ≥55 with B-ALL in CR1 without a plan to proceed to HSCT with CD19-targeted CAR-T with promising initial results: among 14 patients infused to date, no ICANS and no ≥grade 2 CRS was observed [72]. Information about durability of responses is awaited.

The introduction of aggressive prophylactic treatment of the CNS was an early innovation that led to improvement in cure rate in childhood ALL [1]. Modalities available for CNS prophylaxis include intrathecal (IT) chemotherapy, systemic high-dose chemotherapy (methotrexate, cytarabine), and radiation (prophylactic cranial radiation and/or total body irradiation as part of allogeneic transplant conditioning). In adult ALL, CNS relapse has not historically received specific attention largely because poor outcomes generally did not provide opportunity for the CNS to become an issue. Now, with the introduction of novel agents, older patients are surviving long enough to be at risk for CNS relapse. Compounding the problem, novel agents do not penetrate the CNS. Thus, CNS relapses are becoming a more common clinical challenge for older adults. Data are starting to accrue more definitively to support this concern in patients with both Ph+ and Ph− ALL receiving treatment based on novel agents and minimal chemotherapy with approaches to possibly reduce risk of CNS relapse including increasing number of IT chemotherapy treatments, reinstating cranial RT, and re-introducing CNS penetrating chemotherapy [73‒75]. In general, at a minimum, it is recommended that older adults with Ph-negative ALL receive at least 8 instillations of IT chemotherapy with more IT chemotherapy (12–15 instillations) and incorporation of additional treatment modalities considered for patients judged to be at particular risk for treatment failure in the CNS, including patients presenting with hyperleukocytosis at diagnosis and high-risk genetic subtypes such as KMT2A-rearranged. Management of the CNS in older patients with ALL requires ongoing study.

The ability of MRD to predict risk of relapse of ALL is well established in the era of conventional chemotherapy where it is known that MRD that persists after induction or early consolidation predicts for relapse [76‒78]. More sensitive sequencing-based MRD assessment allows for detection of persistent disease at levels lower than 10⁻⁴, providing additional prognostic information [79, 80]. Prognostic information provided by MRD assessment has traditionally guided clinical decision-making regarding need for treatment intensification and treatment change. As more potent novel agents including blinatumomab and inotuzumab are introduced earlier in treatment, including during induction, the ability of early MRD time points to provide prognostic information may be diminished requiring new approaches to identify patients at risk for treatment failure and then develop effective therapeutic management for high-risk patients.

T-cell ALL comprises ∼20% of ALL in older adults with a major management implication being that these patients lack access to novel therapies restricted to CD19 and CD22 expression. Thus, treatment of T-ALL still relies on conventional chemotherapy. Asparaginase is notably active in T-cell ALL with younger adults eligible for pediatric-inspired regimens having excellent outcomes, better than B-cell ALL [14, 81]. However, adults over the age of 50 or 60 years, especially in setting of concurrent comorbidity or obesity, do not tolerate asparaginase-based regimens, even with dose reductions, and need to be considered for alternative approaches [17].

Nelarabine is approved for patients with relapsed T-cell ALL, but data for benefit in adults receiving first-line therapy are mixed [82‒84]. Nelarabine is now routinely incorporated in the treatment of children treated on Children’s Oncology Group (COG) protocols based on the AALL0434 study which demonstrated an improved EFS rate as well as a decrease in CNS relapse, but there were no patients over 30 years included in that study [85]. Although nelarabine may be considered in combination with HCV(A)D based on single-center data, the benefit in older adults is not proven and older adults may be more prone to nelarabine-related neurologic adverse events [83, 86].

T-cell ALL is sensitive to BCL2/BCL-XL inhibition supporting the study of venetoclax-based reduced intensity chemotherapy regimens for newly diagnosed T-cell ALL in older adults [45]. Venetoclax plus HCVD is tolerable in older adults with encouraging early efficacy for untreated patients [45, 51, 54]. There is a clear need for new approaches for T-ALL to enhance the efficacy of conventional and BH3-mimetic-based regimens, with candidates including novel dual BCL2/BCL-XL inhibitors, tyrosine kinase inhibitors (to target LCK), and daratumumab [87, 88]. CAR-T for T-ALL is in development but remains in early phase trials for relapsed disease [89‒93].

Early T-cell precursor (ETP)-ALL is a specific subtype of T-ALL defined immunophenotypically (CD1a-negative, CD8-negative, and absent or dim CD5, with expression of 1 or more myeloid markers) and characterized by myeloid-type mutation profiles and treatment resistance [86, 94‒96]. These patients may respond to venetoclax-based regimens combined with ALL-type chemotherapy and potentially hypomethylating agents [97‒99]. Eligible patients should be strongly considered for HSCT in first remission given adverse biology and dearth of salvage options.

Adverse genetic subtypes are enriched in adult B-ALL negatively affecting outcomes with chemotherapy [6, 7]. A recent study undertook comprehensive molecular characterization of 400 cases of adult ALL employing a combination of single-cell proteogenomics, single-cell RNAseq in addition to clinical diagnostics (cytogenetics/FISH, bulk DNAseq and RNAseq, and chromosomal microarray) [100]. Myeloid clonal hematopoiesis and TP53 mutations were found in 16% and 18% of cases, respectively. Myeloid mutations were associated with older age and prior cytotoxic chemotherapy. In multivariable analysis, age, TP53 mutation, and myeloid mutations were independently associated with inferior OS.

Another study employed sequencing-based evaluation of copy number alterations in addition to conventional karyotyping and found that 76% of patients with TP53 mutation had low hypodiploidy and 98% of low hypodiploid ALL was TP53-mutant [12]. The prevalence of low hypodiploid ALL was strikingly correlated with age, rising from 3% in patients ≤40 years to 32% in patients >55 years. In 33% of cases identified as low hypodiploid, conventional cytogenetics failed to identify the aneuploidy potentially due to inability to culture the leukemia cells in vitro, noteworthy because of the importance of identifying this high-risk subtype for risk adapted therapy.

Longitudinal analyses have demonstrated that both myeloid and TP53 mutations can be found in both lymphoblasts and myeloid cells indicating they are present in stem progenitor cell populations [12, 100, 101]. Therapy-related myeloid neoplasms following treatment for ALL are enriched for TP53 mutations, often present in the preceding ALL, highlighting the multi-lineage potential of ancestral clones and the need to monitor TP53 clonal hematopoiesis during the course of treatment [26, 100, 101]. A recent retrospective study of 875 patients with newly diagnosed ALL treated with HCVAD/HCVD reported that 35 (4%) of patients developed a therapy-related myeloid neoplasm with age ≥60 years and presence of a TP53 mutation at ALL diagnosis predicting for development of this complication [102].

The inferior outcomes of ALL with TP53 or myeloid mutations indicate the need to identify these genetic lesions and report on the outcomes of these subtypes of ALL in clinical trials investigating novel therapeutic approaches. Additionally, novel lineage-focused therapies including CAR-T-directed at CD19 and CD22 will not eradicate stem progenitor cell populations bearing myeloid or TP53 mutations, suggesting that these patients may benefit from HSCT.

ALL may occur secondary to cytotoxic chemotherapy for other cancers and is characterized by suboptimal outcomes following conventional chemotherapy regimens. As with therapy-related myeloid neoplasms, post-therapy ALL is enriched in older adults and is commonly associated with KMT2A/MLL rearrangements, aneuploidy, and TP53 alterations (associated with low hypodiploid/near triploid karyotype) [11, 103, 104].

A unique, increasingly recognized category of therapy-related ALL occurs in patients treated for multiple myeloma with lenalidomide and is associated with a high incidence of TP53 mutations [103, 105‒110]. A two institution retrospective study of 32 ALL cases occurring post-lenalidomide maintenance (median lenalidomide exposure 42 months) reported that all cases were B-ALL, 31/32 Ph−, with a high incidence of TP53 mutations (nearly 50%) and low hypodiploidy [110]. Remarkably, in this cohort, remissions after lenalidomide withdrawal were documented, absent other ALL-directed therapy, although this was a rare occurrence [110]. Lenalidomide leads to IKZF1 and IKZF3 as well as TP53 degradation [111, 112] and has been reported to provide a selective advantage to TP53-mutant hematopoietic cells [113] which may be relevant to the pathogenesis of ensuing cases of ALL. Taken together, the therapeutic exposure(s) preceding the diagnosis of ALL shape the genetic profile of the subsequent leukemia often resulting in high-risk genotypes.

KMT2A/MLL-rearranged ALL is a rare subtype (<10%) of usually B-lineage Ph− ALL associated with high rates of resistance to chemotherapy so that HSCT in CR1 is typically recommended for eligible patients [97, 114]. A specific challenge posed by KMT2A/MLL-rearranged ALL is the risk of lineage-switching and less benefit from lymphoid-lineage-restricted immunotherapies (which may promote lineage switch) [115]. Inhibition of the interaction between KMT2A/MLL and menin represents a lineage-agnostic therapeutic strategy for KMT2A/MLL-rearranged leukemias [116]. The menin inhibitor revumenib was approved by the FDA in November 2024 for the treatment of R/R KMT2A/MLL-rearranged leukemias based on data from AUGMENT-101 showing a CR/CRh rate of 22.8% [117]. This approval represents a welcome therapeutic option and ongoing research is needed to optimize the use of menin inhibitors in frontline therapy.

Outcomes in older adults with newly diagnosed Ph− ALL are improving with the incorporation of novel therapies into upfront treatment including the lineage-restricted immunotherapies for B-ALL (inotuzumab, blinatumomab) and lineage-agnostic therapies (venetoclax) resulting in regimens that are more effective and less toxic. The treatment landscape for older adults with Ph− ALL now ranges from pediatric-inspired chemotherapy (for relatively younger and very fit patients) to entirely chemotherapy-free approaches. HSCT in CR1 continues to play a role for a subset of high-risk patients and the role of CAR-T in frontline therapy represents an area of active research. While further data will continue to refine our ability to tailor treatment based on molecular genetic subtype and MRD response, a reasonable approach is to base initial treatment on disease features, chronologic age, and comorbidities as outlined in Figure 1. Areas of unmet need include T-cell ALL, high-risk genetic subtypes including ALL with TP53 and myeloid-type mutations, therapy-related ALL, CNS disease, and disease that has relapsed after exposure to currently available immunotherapy.

L.M.M. has no conflicts of interest to declare. M.R.L. has received research funding from Novartis and AbbVie and is a consultant for KiTE, Pfizer, Jazz, and Novartis. D.J.D. has received research funding from AbbVie, GlycoMimetics, Novartis, and Blueprint Pharmaceuticals, is a consultant for Amgen, Autolus, Agios, Blueprint, Gilead, Incyte, Jazz, Novartis, Pfizer, Servier, and Takeda and is on the Data Safety Monitoring Board for Daiichi Sankyo and Mt. Sinai MPN Consortium.

The authors received no financial support for the research, authorship, or publication of this article.

L.M.M. and M.R.L wrote the manuscript. L.M.M., M.R.L., and D.J.D. edited the manuscript.