# SOHO State of the Art Updates and Next Questions | Elderly Acute Lymphoblastic Leukemia: Low-Dose Chemotherapy and Immunotherapy Combinations

Perrine Moyer, Aude-Marie Fourmont, Lucie Freiman, Philippe Rousselot, Patrice Chevallier

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## To cite this version:

Perrine Moyer, Aude-Marie Fourmont, Lucie Freiman, Philippe Rousselot, Patrice Chevallier. SOHO State of the Art Updates and Next Questions | Elderly Acute Lymphoblastic Leukemia: Low-Dose Chemotherapy and Immunotherapy Combinations. Clinical Lymphoma Myeloma and Leukemia, 2025, 25 (11), pp.763 - 774. 10.1016/j.clml.2025.06.001. hal-05459712

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# SOHO State of the Art Updates and Next Questions | Elderly Acute Lymphoblastic Leukemia: Low-Dose Chemotherapy and Immunotherapy Combinations

Perrine Moyer,<fnref n="1" /> Aude-Marie Fourmont,<fnref n="1" /> Lucie Freiman,<fnref n="2" /> Philippe Rousselot,<fnref n="2" /> Patrice Chevallier<fnref n="1" />,<fnref n="3" />

## Abstract

There is an unmet medical need for the treatment of elderly patients with acute lymphoblastic leukemia (ALL), as only a minority of them achieves long-term survival with current anti-ALL chemotherapy. Here, the recent management of these patients is discussed, including current approaches and future directions, as novel agents developed for refractory/relapsed ALL are now being incorporated into front-line therapies with very promising results. The manuscript will sequentially consider Philadelphia chromosome (Ph) negative ALL, then Ph+ and finally T-ALL. Accordingly, novel strategies using chemo-free approaches and new drugs such as inotuzumab ozogamicin, blinatumomab, venetoclax, tyrosine kinase inhibitors and CAR T-cells will be discussed.

*Clinical Lymphoma, Myeloma and Leukemia*, Vol. 25, No. 11, 763–774 © 2025 The Authors. Published by Elsevier Inc.
This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))
**Keywords:** Acute lymphoblastic leukemia, Older, Inotuzumab, Blinatumomab, Immunotherapy

## Introduction

Acute lymphoblastic leukemia (ALL) represents the most common cancer in children but is rare in adults. Nevertheless, the incidence of ALL increases after the age of 50 years. Over the past decades, treatment protocols for newly diagnosed adult ALL patients have been intensified on a pediatric basis, leading to significant improvement, especially in terms of overall survival (OS).<fnref n="1" />⁻<fnref n="3" /> Despite these advances, older patients with ALL have not benefited as much as younger patients from pediatric-inspired intensive chemotherapy-based regimens. Indeed, this strategy is severely limited by its toxicity in this population with a dismal 5-year OS (~20%), either in the United States or in Europe.⁴⁻⁹ Other causes can likely contribute to the poor outcomes observed in older ALL patients. First, older adults are less likely than younger ones to achieve complete remission (CR) due to a more aggressive and chemo-resistant disease, with a high incidence of adverse biologic features including low

hypodiploidy/near-triploidy, complex karyotype and BCR:ABL1 or KMT2A (formerly MLL) rearrangements.¹⁰⁻¹² Moreover, the presence of multiple comorbidities in this population (at least one comorbidity in 76% of elderly patients)¹³ and, as a consequence, a reduced capacity to tolerate intensive chemotherapy, leads to high rates of early death during induction (10%-20% in older patients vs. 2%-5% in younger ones).<fnref n="1" />,⁵,⁸,⁹,¹⁴,¹⁵ Even after achieving CR, one-third of patients will die of myelosuppression-associated complications such as infections.⁵,⁶ The definition of “older” or “elderly” patients is also problematic as it is clear that outcomes worsen with increasing age and patients in their 60s, seventies or eighties are not the same. Most clinical trials set the threshold at 55 to 60 years old to define such patients because of a reduced tolerance to chemotherapy after this age.¹⁶ However, while the youngest of them can be considered for intensive chemotherapy, palliative care only has often been recommended for those over 75.¹⁷ Indeed, OS is very poor for these patients, less than 10% at 3 years, with or without chemotherapy.⁷,¹⁴,¹⁸

Hopefully, several safe and effective non-chemotherapeutic agents have been developed over the last decade. Here, the results of chemo-free approaches and the use of targeted therapies or immunotherapies in combination with low-intensity chemotherapy in older/elderly (both terms will be used below) patients with ALL is updated and discussed,¹⁹,²⁰ providing also future directions that can improve the outcomes of this high-risk population.

<footnote n="1">¹Hematology Department, Nantes University Hospital, Nantes, France</footnote>

<footnote n="2">²Division of Hematology, Centre Hospitalier de Versailles, Université Versailles Paris-Saclay, Le Chesnay, France</footnote>

<footnote n="3">³CRCI2NA, INSERM UMR 1307 & CNRS UMR 6075, IRS_UN, University of Nantes, France</footnote>

<footnote>Submitted: Apr 17, 2025; Revised: May 31, 2025; Accepted: Jun 2, 2025; Epub: 6 June 2025</footnote>

<footnote>Address for correspondence: Patrice Chevallier, MD, PhD, Service d'Hématologie Clinique, CHU Hotel-Dieu, Place A. Ricordeau, 44093 Nantes Cedex, France.
E-mail contact: patrice.chevallier@chu-nantes.fr</footnote>
## Philadelphia Chromosome-Negative (Ph-) B-Cell ALL

The most important contribution of immunotherapy has been for patients with Philadelphia chromosome (Ph)-negative B-cell ALL (B-ALL). Two main agents have been developed, respectively blinatumomab, a CD3/CD19 bispecific T-cell engager (BiTE) antibody, and inotuzumab ozogamicin, a CD22-directed antibody conjugated to the antitumor antibiotic calicheamicin. First introduced as salvage treatments in the refractory/relapsed (R/R) setting, both are now developed in frontline therapy in older patients with Ph- B-ALL, thus allowing a reduced exposure to chemotherapy.

### Blinatumomab

Blinatumomab is approved in monotherapy for R/R CD19+ B-ALL but also for patients with positive measurable residual disease (MRD+), in first line or later, based on the results of the TOWER²¹ and BLAST²² trials, respectively. The Food and Drug Administration (FDA) in the USA also recently approved its administration frontline in consolidation for MRD negative (MRD-) patients, both in children and adults, with Ph- B-ALL,²³ based on 2 prospective studies (Table 1).²⁴,²⁵

From the R/R setting, it has been shown that blinatumomab, compared to salvage chemotherapy, provides a better remission rate (34% vs. 16%, *P* < .001), higher event-free survival (EFS; 6-month estimates, 31% vs. 12%, *P* < .001), as well as longer median duration of remission (7.3 vs. 4.6 months) and OS (7.7 vs. 4.0 months, *P* = .01).²¹ It is also known that patients with a lower disease burden (< 50% of bone marrow [BM] blasts) obtain the best response rates with blinatumomab, and have a lower incidence of severe adverse events (AEs), such as cytokine release syndrome (CRS) or immune-effector cell-associated neurotoxicity syndrome (ICANS),²¹,²⁶ two of the main complications of BiTEs. In a recent study,²⁷ relapsed patients who directly received blinatumomab had a shorter relapse-free survival and OS than those bridged to blinatumomab, reinforcing the fact that blinatumomab administered alone in monotherapy is likely more appropriate for consolidation than induction therapy.

Focusing on the front-line setting, the direct use of blinatumomab in monotherapy for induction also does not appear to be the best option. This is suggested by a recent Phase 2 prospective trial of the Southwest Oncology Group (SWOG)²⁸ study which included 29 newly diagnosed older patients with Ph- B-ALL (age ≥ 65 years, median age 75 years). Blinatumomab was used for induction (1 or 2 cycles) and consolidation (3 cycles), as a chemo-free regimen and was followed by 18 months POMP maintenance (6-mercaptopurine [6-MP], vincristine, methotrexate [MTX] and prednisone). The CR rate was 66%, in spite of a median baseline BM blast percentage of 87%, but the 3-year estimated OS rate was only 37%. Blinatumomab was well tolerated in this population with only one grade 3 CRS and one grade 3 ICANS.²⁸ Such data (blinatumomab in monotherapy for induction) is not available in younger patients with Ph- B-ALL.

Blinatumomab could therefore be more efficient in combination with low-dose chemotherapy for induction. Some data are already published for younger patients²⁹,³⁰ and other studies are ongoing (NCT03914625) or will start soon (GRAALL 2024,

<table><caption>Table 1 Front-Line Use of Blinatumomab for Ph-Negative B-ALL.</caption><thead><tr><th>Study</th><th>Treatment Regimen</th><th>N</th><th>Median Age (range), Years</th><th>Response, %</th><th>Overall Survival, % (year)</th><th>Relapse Rate, %</th><th>Safety Outcomes</th></tr></thead><tbody><tr><td>SWOG 1318<sup>28</sup><br>(NCT02143414)</td><td>Induction/Conso blinatumomab Maintenance: POMP</td><td>29</td><td>75 (66-84)</td><td>CR/CRI: 66% MRD-negative (flow cytometry): 92%</td><td>37% (3 y)</td><td>42%</td><td>Grade ≥ 3 CRS 3%<br>Grade ≥ 3 NE 3%<br>Early death: 0%<br>Death in remission: 0%</td></tr><tr><td>GMALL BOLD<sup>31</sup><br>(NCT03480438)</td><td>Induction: chemo+ blinatumomab Conso: chemo+ blinatumomab Maintenance: POMP</td><td>47</td><td>66 (56-76)</td><td>CR/CRI: 85% MRD-negative: 88%</td><td>80% (1 y)<br>67% (3 y)</td><td>15%</td><td>Grade ≥ 3 CRS: unknown<br>Grade ≥ 3 NE: unknown<br>Early death: 4%<br>Death in remission: 6%</td></tr><tr><td>GOLDEN GATE<br>(NCT04994717)</td><td>Randomized Induction blinatumomab + low chemo vs. SOC chemo Conso Maintenance</td><td>-</td><td>≥55 y (or 40 to &lt;55 y with severe, pre-defined comorbidities)</td><td></td><td></td><td>Results pending</td><td></td></tr></tbody></table>

**Abbreviations:** Chemo = chemotherapy; Conso = consolidation; CRS = cytokine release syndrome; CR = complete remission; CRI = complete remission with incomplete count recovery; MRD = measurable residual disease; NE = neurological events; POMP = 6-mercaptopurine; vincristine; methotrexate, prednisone; SOC = standard of care; y = years.
NCT06860269). In older patients, the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL) has reported at the 2023 ASH meeting the preliminary results of the phase 2 BOLD study.31 This study evaluated the response rate after an induction consisting of one cycle of low-dose chemotherapy (vincristine, idarubicin and dexamethasone) plus one cycle of blinatumomab. Induction was followed by 3 further blinatumomab cycles, alternating with age-adapted consolidation chemotherapies, and standard maintenance (6-MP/MTX), up to a total treatment duration of 2 years. The median age was 66 years (range 56-76), and 47 patients were evaluable, showing a promising response rate of 85%, with negative MRD for 88% of responders. This regimen was well tolerated, with only 4% of early death (including 2 patients who died of infection). With OS after 1 and 3 years of 80% and 67%, respectively, this strategy compared favorably with historical cohorts of elderly patients receiving intensive chemotherapy-based regimen.31 The interest of combining blinatumomab and low dose chemotherapy will hopefully be fully established by a phase III comparative prospective study such as the ongoing randomized GOLDEN GATE trial (NCT04994717) which is currently recruiting. A safety run-in of the first 10 patients included has been reported showing that this regimen was well tolerated (no early death) and effective (all patients were in CR and 90% were MRD-).32

At variance from younger patients,22,33-37 data regarding the use of blinatumomab for MRD+ or MRD- patients are still scarce in older patients. Recently, the results of the ECOG-ACRIN E1910 study (NCT02003222) have been published.24 This phase III trial randomized patients with Ph- B-ALL (median age 51 years, range 30-70 years) who achieved an MRD- status after induction, to receive or not 4 courses of blinatumomab added to conventional chemotherapy consolidation in the front-line setting. The authors reported a significantly better OS in patients treated with blinatumomab (3-year OS rate 85% vs. 68%). Among the 93 patients aged 55 years or more, blinatumomab appeared to improve 3-year OS (70% vs. 65%) in a lower range as compare to younger patients and yet without statistical significance.24

*In summary*, lower leukemia burden maximizes the impact of blinatumomab therapy in Ph- B-ALL patients.38 Blinatumomab should not be used alone for induction but rather be combined to low dose chemotherapy or used as consolidation in Ph- B-ALL patients, including older ones. The GOLDEN GATE trial, if positive, could establish a new standard of care for older Ph- B-cell ALL patients. Moreover, in the close future, subcutaneous blinatumomab may replace the continuous infusion formulation, allowing to improve quality of life and reduce hospital visits.39 Finally, AZD0486, a novel IgG4 fully human CD19-CD3 bispecific antibody may be interesting to reduce the incidence of CRS, as reported in lymphoma,40 and is currently evaluated for R/R B-ALL (NCT06137118).

## Inotuzumab Ozogamicin

Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to calicheamicin,41,42 is approved for R/R CD22+ B-cell ALL, based on the randomized phase III INO-VATE trial, which included 279 patients (median age 47 years, range 18-

78, 39% of them 55 years or older). This trial showed that inotuzumab ozogamicin was associated with better CR (73% vs. 35%) and MRD- (78% vs. 28%) rates and an improved 2-year OS (22.8% vs. 10%), compared to conventional salvage chemotherapies.43,44 Median progression-free survival (PFS) was improved but lasted only for a few months (5 months). A comparison of younger and older patients (cut-off 55 years) was performed retrospectively, showing no significant difference in terms of response and MRD-rates nor median duration of response (DOR) between inotuzumab ozogamicin and chemotherapy regimen. However, median OS was better for younger patients (OS 8.6 vs. 5.6 months), but not for older ones, with Ino.45 Patients receiving inotuzumab ozogamicin are moreover at a greater risk of developing veino-occlusive disease (VOD) also known as sinusoidal obstruction syndrome (SOS).46 This risk was not increased in the subgroup of elderly patients in the INO-VATE study (15% vs. 13% in younger patients).45 Yet, among patients who proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT), 10 (17%) aged <55 years vs. 7 patients (41%) aged ≥55 years developed VOD after post-study allo-HSCT. Significant risk factors for SOS/VOD after allo-HSCT were however recognized not to be age but conditioning with double alkylators and previous allo-HSCT after first-line therapy (Table 2).43,47

Finally, inotuzumab ozogamicin is able to provide a high rate of CR even in patients with high disease burden43,48 and extramedullary disease.47 The CR rate reached 77% for patients with > 50% of BM blasts in the INO-VATE study while it was only 34% overall with blinatumomab in the TOWER study.21 Even if no comparison of the 2 drugs has been performed so far in the R/R setting, this suggests that inotuzumab ozogamicin is probably more efficient to achieve a better debulking than blinatumomab.

This observation leads to consider an inotuzumab ozogamicin-based therapy as the best choice for first-line induction, especially in older patients, and the results of several studies are now available.49 First, a single-center phase II study was performed at the MD Anderson Cancer Center (MDACC).50 This trial recruited 80 patients with newly diagnosed Ph- B-cell ALL. The median age was 68 years (range 60-87) and 35% of the patients were aged 70 years or older. A combination of intotuzumab ozogamicin with reduced-dose of cyclophosphamide, dexamethasone and methotrexate (mini-hyper-CVD regimen) was used, followed by POMP maintenance. Initially, the total dose of intotuzumab ozogamicin was 5.7 mg/m² (1.8 mg/m² cycle 1 at Day (D) 3, then 1.3 mg/m² also at D3 for subsequent cycles), then, in order to decrease the liver toxicity seen in the first 50 patients, this total dose was reduced to 2.7 mg/m² (0.6 mg/m² at D2 + 0.3 mg/m² at D8 during cycle 1, then 0.3 mg/m² at D2 + 0.3 mg/m² at D8 during cycles 2-4). After a second protocol amendment, 4 cycles of blinatumomab were added as a consolidation, replacing 4 cycles of chemotherapy, and POMP maintenance was reduced to 12 cycles, integrating 1 cycle of blinatumomab every 3 POMP cycles. The overall response rate (ORR) was 98% (only one patient with tetraploidy did not respond). MRD negativity, assessed by flow cytometry, was achieved in 94% of the responders. The 2-year and 5-year OS rates were 64% and 46%, respectively. The most common grade 3-4 AEs were thrombocytopenia in 78% of patients and febrile neutropenia in
<table><caption>Table 2 Front-Line Use of Inotuzumab for Ph-Negative B-ALL.</caption><thead><tr><td>Study</td><td>Treatment Regimen</td><td>N</td><td>Median Age (Range), Years</td><td>Response, %</td><td>Overall Survival, % (year)</td><td>Relapse Rate, %</td><td>Safety Outcomes</td></tr></thead><tbody><tr><td>MDACC<sup>50</sup> (NCT01371630)</td><td>Induction: InO (max 5.7 then 2.7 mg/m²) + mHCVD<br>Conso: blina<br>Maint: POMP + blina</td><td>80</td><td>68 (60-87)</td><td>CR/CRp/CRi: 99%<br>MRD-negative (flow cytometry): 94%</td><td>63.6% (2 y)<br>46% (5 y)</td><td>15%</td><td>SOS: 8%<br>Early death: 0% (4 wk), 3% (8 wk)<br>Death in remission: 44%</td></tr><tr><td>GMALL INITIAL-1<sup>51</sup> (NCT03460522)</td><td>Induction: InO (max 4.8 mg/m²) + Dex (x3 cycles)<br>Consol: chemo<br>Maint: POMP</td><td>43</td><td>64 (56-80)</td><td>CR/CRi: 100%<br>MRD-negative (IG/TR PCR): 71%</td><td>91% (1 y)<br>73% (3 y)</td><td>27%</td><td>SOS: 2%<br>Early death: 0%<br>Death in remission: 17%</td></tr><tr><td>EWALL-InO<sup>52</sup> (NCT03249870)</td><td>Induction: InO (max 2.8 mg/m²) + CVD (x2 cycles)<br>Conso: chemo<br>Maint: POMP</td><td>131</td><td>68 (55-84)</td><td>CR/CRp: 90%<br>MRD-negative (IG/TR PCR): 80%</td><td>73% (1 y)<br>55% (2 y)</td><td>38%</td><td>SOS: 1%<br>Early death: 2%<br>Death in remission: 13%</td></tr><tr><td>Alliance A041703<sup>53</sup> (NCT03739814)</td><td>Induction: InO (max 4.2 mg/m²)<br>Conso: blina<br>Maint: blina</td><td>33</td><td>71 (60-84)</td><td>CR/CRh/CRi: 97%</td><td>84% (1 y)</td><td>27%</td><td>SOS: 3%<br>Early death: 0%<br>Death in remission: 6%</td></tr><tr><td>Alliance A042001 (NCT05303792)</td><td>Randomized<br>Induction: InO + mHCVD vs. hyper-CVAD (age adjusted)<br>Conso: blina Maint: POMP</td><td>-</td><td>≥ 50 y</td><td></td><td></td><td>Results pending</td><td></td></tr></tbody></table>

**Abbreviations**: Blina = Blinatumomab, chemo = chemotherapy, Conso = consolidation, CR = complete remission, CRi = complete remission with incomplete count recovery, CRp = complete remission with incomplete platelet recovery, Dex = dexamethasone, IG/TR = immunoglobulin and T-cell receptor, InO = Inotuzumab ozogamicin, Maint = maintenance, mHCVD = mini-hyper-CVD regimen (cyclophosphamide, vincristine, dexamethasone), MRD = measurable residual disease, PCR = polymerase chain reaction, POMP = 6-mercaptopurine, vincristine, methotrexate, prednisone, SOS = sinusoidal obstruction syndrome, y = years.
32%. Six (8%) patients developed VOD/SOS during the first dose levels. VOD/SOS were abrogated with more fractionated schedules of inotuzumab ozogamicin. No death occurred during induction therapy but 35 patients (44%) died in remission, due to infections (n = 8, 10%) or secondary myeloid neoplasm (n = 9, 11%). The number of deaths in remission increased with age at 45% (n = 5/11) for patients aged between 60 and 64 years, 81% (n = 13/16) in the 65-69 years range and 85% (n = 17/20) for patients over 70, showing that the toxicity of the procedure increase with age. Surprisingly, the use of blinatumomab did not significantly improve PFS nor OS compared with the outcomes of the 50 first patients who did not receive blinatumomab before the protocol amendment.⁵⁰

The front-line chemo-free approach with inotuzumab ozogamicin has been tested by the GMALL group. This phase II study (INITIAL-1 trial)⁵¹ included 45 patients (median age 64 years, range 56-80) with a newly diagnosed CD22+ Ph- B-cell ALL. Patients received up to 3 induction cycles of inotuzumab ozogamicin with dexamethasone only. The first induction cycle (21 days) consisted of inotuzumab ozogamicin 0.8 mg/m² at D1, then 0.5 mg/m² at D8 and D15 in combination with dexamethasone 10 mg/m² per day D7-8 and D14-17. The second and third induction cycles (28 days) consisted of inotuzumab ozogamicin 0.5 mg/m² at D1, D8, and D15. The cumulative dose of inotuzumab ozogamicin was 4.8 mg/m². After achieving CR, patients received up to 5 cycles of age-adapted consolidation chemotherapy followed by 1 cycle of re-induction therapy and a maintenance with 6-MP and MTX for a total treatment duration of 2 years. All patients reached CR or CR with incomplete hematologic recovery, of whom 71% achieved a MDR-negative status (evaluated by IG/TR PCR) after 3 cycles of induction. The 3-year OS, non-relapse mortality and relapse rates were 73%, 17%, and 27%, respectively. No patient died during the first 6 months following induction and only one experienced a non-fatal VOD/SOS after cycle 2, demonstrating the safety of this chemo-free induction approach.

The European Working Group on Adult ALL (EWALL) has recently reported the results of the phase II multicenter EWALL-INO trial which included 131 patients aged ≥ 55 years (median 68 years, range 55-84) with a newly diagnosed Ph- CD22+ B-cell ALL who received inotuzumab ozogamicin in combination with a low-dose chemotherapy induction.⁵² After a prephase of corticosteroids, the first induction consisted of vincristine once weekly for 4 weeks, dexamethasone once daily for 2 days every week for 4 weeks, and 3 injections of inotuzumab ozogamicin once weekly for 3 weeks (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). It was followed by a second induction combining cyclophosphamide once daily for 3 days, dexamethasone once weekly for 2 weeks, and 2 injections of inotuzumab ozogamicin once weekly for 2 weeks (0.5 mg/m² D1 and D8). Thus, the total dose of inotuzumab ozogamicin was 2.8 mg/m². Then, responders received up to 6 cycles of consolidation with age-adapted chemotherapy and an 18-month POMP maintenance. Allo-HSCT was allowed after 6 cycles of consolidation, then, following an amendment, after 3 cycles of consolidation. The CR/CRp (CR with incomplete platelet recovery) was 90% and a MRD negativity (assessed by IG/TR PCR) was achieved in 80% of responders after the 2 inductions. One- and 2-year OS rates

were 73% (primary objective reached, hypothesis > 60%) and 55%, respectively. The cumulative incidence of relapse was 25% at 1 year and 38% at 2 years. The safety profile was good as only 3 deaths occurred during induction 1 (2%) and no death was documented during induction 2. Grade 4 neutropenia and grade 3 to 4 thrombocytopenia were documented in 87% and 100%, and in 22% and 12% of patients during inductions 1 and 2, respectively. Only one VOD/SOS (grade 3) was documented (during induction 1) and resolved under defibrotide. Overall, 35% of patients died after relapse (main cause of death) and 13% died in remission (mainly of infections). This very large international study and the good survival achieved allowed also identifying some prognostic factors. High-risk cytogenetics was associated with lower OS (hazard ratio [HR], 2.90, *P* < .001), higher CD22 expression (≥ 70%) with higher OS (HR, 0.52, *P* < .03), and MRD positivity (>10⁻⁴) after the second induction with lower relapse-free survival (HR, 2.61, *P* < .02) and higher risk of relapse (HR, 3.82, *P* < .004).⁵² Patients receiving allo-HSCT as consolidation (n = 10) had very good outcomes (2-year OS and PFS 90% for both), suggesting that allo-HSCT can be of interest in some patients.

Finally, the Alliance A041703 study combined inotuzumab ozogamicin and blinatumomab in a chemo-free approach. As of now, only preliminary results are available.⁵³ Inclusion criteria were patients aged ≥ 60 years with a newly diagnosed Ph- CD22+ B-cell ALL, and allo-HSCT was excluded. The first induction consisted of inotuzumab ozogamicin 0.8 mg/m² at D1, then 0.5 mg/m² at D8 and D15 during a 21-day cycle. Then, a second 28-day induction was programmed with inotuzumab ozogamicin at 0.5 mg/m² D1, D8, D15 in case of CR/CRi or inotuzumab ozogamicin 0.8 mg/m² at D1 and 0.5 mg/m² at D8 and D15 in case of no response after cycle 1. The maximum cumulative dose of inotuzumab ozogamicin was 4.2 mg/m². After the 2 inductions, patients were programmed to receive blinatumomab in consolidation for 3 to 4 cycles. Results of the first 33 patients (median age 71 years) have been presented, showing a CR rate of 85% after inotuzumab ozogamicin and of 97% after inotuzumab ozogamicin+blinatumomab. The 1-year OS was 84%. Overall, 9 (27%) patients relapsed and 9 (27%) died (6 after relapse, 2 in remission and 1 without remission due to respiratory failure in a context of hepatic VOD/SOS).⁵³

In summary, the combination of inotuzumab ozogamicin with low dose chemotherapy or the inotuzumab ozogamicin chemo-free approach both represent very promising front-line induction therapies for older patients with Ph- B-ALL. OS has almost doubled compared to that obtained with chemotherapy alone in all phase II studies published so far. High-risk patients can be now identified on the basis of cytogenetics, MRD or CD22 expression at diagnosis, which could help to determine which patients could benefit of a more intensive treatment, including allo-HSCT, in the future. As for blinatumomab, prospective comparative studies are required to demonstrate the superiority of inotuzumab ozogamicin front-line over a standard induction chemotherapy. A randomized phase II study (Alliance A042001 trial, NCT05303792) is currently ongoing for this purpose. It remains to mention that the use of inotuzumab ozogamicin in front-line appears safe enough for older patients, as the rate of VOD/SOS is relatively low (1 to 8%, mostly not
# Chemo-immunotherapy in ALL of elderly patients

severe, when it reached 14% for R/R ALL patients in the INO-VATE trial).⁴³,⁴⁶ Even if a lower rate of allo-HSCT was performed in front-line studies (5%-23%, when it was 44% in the INO-VATE trial), the occurrence of VOD/SOS after this procedure was not a matter of concern, while in contrast allo-HSCT represents the major factor associated with VOD/SOS in patients receiving inotuzumab ozogamicin in the R/R setting. The pathophysiology of VOD/SOS associated with inotuzumab ozogamicin is not fully explained, but similar risks have been described with gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody also conjugated to calicheamicin.⁵⁴ One of the hypotheses is that calicheamicin could be directly toxic to sinusoidal endothelial cells in the liver.⁵⁵ Besides recommendations for prevention and management of the risk of VOD/SOS with inotuzumab ozogamicin,⁵⁶ the development of less toxic anti-CD22 therapeutic antibodies could be of interest. Thus, Adct-602, a new anti-CD22 antibody conjugated to the pyrrolobenzodiazepine (PBD) dimer cytotoxin, is currently under investigation in patients with R/R B-cell ALL.⁵⁷ Preliminary results in 21 heavily pre-treated patients (median age 39 years, range 21-82) who received this compound showed that none of them developed VOD/SOS.⁵⁷

## Venetoclax

Venetoclax is an oral therapy developed to selectively target the anti-apoptotic protein BCL-2. This drug is approved for the treatment of patients with newly diagnosed acute myeloid leukemia and ineligible for intensive chemotherapy. It is also approved for several types of B-cell lymphomas. BCL-2 inhibition leads to activation of the intrinsic apoptotic pathway, ultimately resulting in cell death.⁵⁸ It has been demonstrated by preclinical data that malignant B and T-lymphoblasts are BCL2-dependent and sensitive to venetoclax,⁵⁹⁻⁶¹ even in cases with high-risk genetics such as *KMT2A-rearrangement*⁶² or *hypodiploidy*.⁶³ Thus, venetoclax can synergize and enhance the efficacy of chemotherapy, allowing also for dose reduction lessening toxicity. Therefore, venetoclax combination therapies are now being evaluated, in both younger and older patients, and in both front-line and R/R settings.

As for blinatumomab and inotuzumab ozogamicin, the results seem to be not optimal for patients with R/R ALL. MDACC⁶⁴ conducted a phase 1/2 study where 22 patients with R/R ALL (median age 46 years, range 20-70, with 4 patients aged 60 or over) received the mini-hyper-CVD regimen (attenuated doses of cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on D1 to D14 in cycle 1 and on D1 to D7 in consolidation cycles. The CR/CRi rate was 57% and 45% of responders achieved a MRD-negative status evaluated by multiparameter flow cytometry. The median DOR was 6.3 months, median OS 7.1 months, and 1-year OS rate 29%. The most common grade ≥3 non-hematologic AEs were infections in 17 patients (77%) and febrile neutropenia in 4 (18%).

Results seem more promising for newly-diagnosed patients. Thus, a phase I trial conducted by the Dana-Farber Cancer Institute (DFCI) enrolled 19 patients with ALL, either at diagnosis (≥ 60 years $n = 11$, B-cell $n = 8$ and T-cell $n = 3$) or R/R (≥ 18 years $n = 8$, B-cell $n = 3$ and T-cell $n = 5$).⁶⁵ The treatment consisted of several 21 day cycles of venetoclax daily with mini-hyper-CVD

regimen followed by POMP maintenance for 2 years with venetoclax daily. Tolerability was excellent with no dose limiting toxicities, no deaths during the first 60 days and no treatment discontinuation for toxicity. Venetoclax 600 mg daily was identified as the recommended dose for further phase II studies. The most common non-hematologic AEs were grade ≥ 3 infections. The eleven older patients treated at diagnosis had a very good outcome since 10 (91%) achieved CR and MRD negativity (<10⁻⁴ by flow cytometry). Median disease-free survival (DFS) was 54.6 months, 2-year DFS 90%, while median OS was not reached and 2-year OS 82%. A median follow-up of 60 months allowed to study the 5-year OS rate which was 55%.

In *summary*, based on the phase I study reported above, the combination of venetoclax with low-dose chemotherapy, especially the mini-hyper-CVD regimen, appears promising in newly diagnosed older patients with Ph- B-ALL. These observations have to be confirmed by phase II/III studies and other chemotherapy regimen could be tested. A multi-centric phase II study is already ongoing (NCT03319901) and preliminary results have shown that of 30 newly diagnosed patients with B- or T-ALL patients (median age 68 years, range 57-81), 25 (83%) achieved MRD negativity while the early death rate was only 3% ($n = 1$) and the estimated 1-year and 2-year OS rates 82.1% and 74.6%, respectively.⁶⁶ Combining venetoclax with other proapoptotic agents, such as navitoclax, a BCL-XL/BCL2 inhibitor, may also be part of the armamentarium in the future.⁶⁷

## Anti-CD19 CAR T-Cells

Along with blinatumomab, CD19-directed chimeric antigen receptor (CAR) T-cells is another immunotherapy targeting CD19 in B-cell ALL. Experience about this immunotherapy is still scarce in older patients with B-ALL. Two autologous anti-CD19 CAR T-cell, the CD28 costimulatory domain-based brexucabtagene autoleucel (brexu-cel) and the 4-1BB costimulatory domain-based obecabtagene autoleucel (obe-cel), are now approved by FDA in the US for adults older than 25 with R/R B-ALL. This is based on the results of the multicenter phase II ZUMA-3 trial⁶⁸ and the more recent phase I/II FELIX study,⁶⁹ respectively. The outcome of 15 patients treated with brexu-cel aged 60 or more (range 60-84) was reported as part of an update study.⁷⁰ Response and outcome were particularly interesting in this cohort with an overall CR rate of 86.7%, a median relapse-free (RFS) survival of 14.4 months and a median OS of 47 months. In terms of tolerance, long-term safety was favorable, with no alert signals (33% CRS grade ≥ 3 and 22% ICANs). In the FELIX study, 25 patients were aged ≥ 65 yo (range: 65-81), of whom 24 (96%) achieved CR/CRi after receiving obe-cel.⁶⁹ There is no data on the use of CAR T-cells in first-line therapy for older patients. However, a phase I single-center, one-arm, non-randomized study is ongoing (NCT05707273) where CAR-T cells are tested in consolidation phase after achieving CR in patients 55 years or older with B-cell ALL, regardless of the MRD status and with no intention to proceed to allo-HSCT.⁷¹

*In summary*, the role of anti-CD19 CAR T-cells therapy remains to be established in older patients but could represent an alternative to the chemotherapy used in consolidation after blinatumomab or inotuzumab ozogamicin. The problem of relapse after CAR T-cell therapy, which is frequent in the R/R setting,⁷² needs to be evaluated
also in front-line. Other formulations may be of interest, such as anti CD22 CAR T-cells, or bi-specific anti CD19/CD22 CAR T-cells,⁷³,⁷⁴ for patients who have already received blinatumomab or have lost CD19 expression at relapse.

# Philadelphia Chromosome-Positive (Ph+) B-Cell ALL

## Tyrosine-Kinase Inhibitors (TKI) and Chemotherapy

The BCR:ABL1 gene rearrangement, leading to Ph+ ALL, is detected in around 45% of B-ALL cases occurring after the age of 65 years,⁷⁵ thus representing the most common ALL subtype in elderly patients. Historically, intensive chemotherapy followed by allo-HSCT was the standard of care for Ph+ ALL.⁷⁶ However, elderly patients often exhibit reduced tolerance to such procedures. Hopefully, the advent, 25 years ago, of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of this population, initially with the first-generation TKI imatinib,⁷⁷ then with second-generation TKIs, such as dasatinib and nilotinib.⁷⁸,⁷⁹ Finally, ponatinib, a third generation TKI, appears to be even more efficient, as demonstrated by the recent results of the PhALLCON study (NCT03589326).⁸⁰ This phase III trial, comparing front-line ponatinib versus imatinib with reduced-intensity chemotherapy, included 245 newly diagnosed Ph+ ALL patients, of whom 91 (37,1%) were aged 60 or over (ponatinib *n* = 61; imatinib *n* = 30). A benefit was observed for ponatinib vs. imatinib across all subgroups analyzed for MRD-negative CR, including that of older patients (40.0% vs. 10.3%; relative risk, 3.87; risk difference, 0.30; *P* < .001). Moreover, the combination of ponatinib with reduced-intensity chemotherapy was not associated with excessive toxicity. These results suggest that this combination could become a new standard of care in elderly patients with Ph+ALL.⁸¹

## The Chemo-Free Approach: Combination of TKI and Immunotherapy

Given the high efficacy of TKIs together with the advent of immunotherapy, the need for chemotherapy has been more and more questioned in elderly patients with Ph+ ALL. The GIMEMA group pioneered a chemo-free approach (imatinib or ponatinib + steroids) in this setting,⁸²,⁸³ which led the combination of TKI and blinatumomab to become the treatment of choice for these patients, based on very encouraging results of phase II/III studies. Thus, the phase II D-ALBA trial (NCT02744768) treated newly diagnosed patients with Ph+ ALL (no upper age limit) with an induction course of dasatinib and steroids, followed by at least 2 cycles of blinatumomab consolidation. The initial report showed a molecular response rate after the first 2 blinatumomab cycles of 60% in the 63 patients considered for analysis (median age 54 yo, range 24-82).⁸⁴ The final report showed a 5-year OS of 80%, with 29 patients achieving durable CR without chemotherapy nor allo-HSCT.⁸⁵ Another phase II study evaluated the feasibility of combining dasatinib, steroids and blinatumomab in 24 newly diagnosed patients with Ph+ ALL over 65 (median age of 73 years, range 65-87).⁸⁶ With an induction of dasatinib/prednisone, a consolidation of 3 cycles of blinatumomab/dasatinib and maintenance with dasatinib/prednisone, 3-year OS and EFS were, respectively, of 87% and 77%. Data are also available about the combi-

nation of ponatinib and blinatumomab. In a phase II trial from the MDACC,⁸⁷ up-dated in 2024,⁸⁸ the 2 drugs were given in combination for up to five 42-day cycles followed by ponatinib monotherapy in maintenance. Among 60 patients treated, including 38% over 60, with either newly diagnosed Ph+ ALL (67%), R/R Ph+ ALL (23%) or chronic myeloid leukemia in lymphoid blast crisis (10%), the complete molecular response rate evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) was 83% (67% at the end of course one), and the rate of MRD-negative status evaluated by next-generation clono-sequencing was 98% (45% at the end of course one). With a median follow-up of 24 months, the estimated 3-year OS rate was 91% and the EFS rate was 77%. Impressively, older patients had a 3-year EFS of 80% with no difference compared to younger ones (74%, *P* = .41). In favor of the chemo-free approach, the addition of mini-hyper-CVD did not appear to improve the outcome of the blinatumomab/ponatinib combination, as reported by the same group with a 3-year OS of 76%.⁸⁹ A phase III study is also ongoing in Italy (NCT04722848) comparing, in front-line, ponatinib followed by blinatumomab vs. imatinib plus chemotherapy. Preliminary results presented during the ASH 2024 meeting⁹⁰ showed 73% of MRD response at the end of the second blinatumomab cycle. The combination was well tolerated, even in the older population (27% of the cohort). Unfortunately, the EWALL-PH03 trial (NCT04688983), a randomized phase II study comparing the safety and efficacy of ponatinib in combination with either chemotherapy or blinatumomab, versus imatinib plus chemotherapy, as frontline therapy for patients over 55 years, had to stop prematurely because of a very slow accrual (Table 3).

Conversely to blinatumomab, data regarding the use of inotuzumab ozogamicin in combination with TKI are scarce in Ph+ ALL with only information in the R/R setting. Beside cases reports,⁹¹⁻⁹³ results of the combination inotuzumab ozogamicin + bosutinib, a second generation TKI, have been reported in 18 patients with a median age of 62 years (range 19-74), showing a CR/CRi rate of 83%, complete molecular response in 56% of the patients, no mortality within the first 30 days, and, with a median follow-up of 44 months, median DOR and OS of 7.7 months and 13.5 months, respectively.⁹⁴ These results appear better than those obtained with inotuzumab ozogamicin in monotherapy.⁹⁵ Of note, 2 patients have been reported, of respectively 51 and 67 years, who both achieved complete molecular remission without CRS after receiving a chemo-free salvage regimen combining inotuzumab ozogamicin and blinatumomab for R/R Ph+ ALL,⁹⁶ a combination that could be of interest also in front-line for older patients with Ph+ALL.

## Resistance to TKI and CNS Involvement

One of the issues with chemo-free regimens is the lack of central nervous system (CNS) diffusion. Indeed, imatinib and ponatinib showed poor capacities to cross the blood-brain barrier,⁹⁷,⁹⁸ while dasatinib might exhibit a better efficacy on CNS leukemic involvement.⁹⁹ The efficacy of blinatumomab on such extra-medullary disease is also ill-known since patients presenting with leukemic blasts in the cerebrospinal fluid were often excluded from initial clinical trials with this bispecific antibody, and the same is true for inotuzumab ozogamicin. The consequence is that several isolated
<table><caption>Table 3 Front-Line Use of Blinatumomab for Ph-Positive B-ALL.</caption><thead><tr><th>Study</th><th>Treatment Regimen</th><th>N</th><th>Median Age (Range), Years</th><th>Response, %</th><th>Overall Survival, % (year)</th><th>Relapse Rate, %</th><th>Safety Outcomes</th></tr></thead><tbody><tr><td>GIMEMA<br>D-ALBA trial<sup>85</sup><br>(NCT02744768)</td><td>Induction:<br>Dasa + steroids<br>Conso: Blina</td><td>63</td><td>54 (24-82)</td><td>CR: 98%<br>MRD-negative<br>(BCR:ABL):<br>93%</td><td>80,7 % (4y)</td><td>14%</td><td>Grade ≥ 3 CRS: 0%<br>Grade ≥ 3 NE:1,5%<br>Early death : 1,5 %<br>Death in remission :<br>3%</td></tr><tr><td>SWOG<sup>86</sup><br>(NCT02143414)</td><td>Induction :<br>Dasa + steroids<br>Conso : Dasa + Blina (x3 cycles)<br>Maint :<br>Dasa + steroids</td><td>24</td><td>73 (65-87)</td><td>CR: 92%<br>MRD-negative<br>(Flow cytometry):<br>89%</td><td>87% (3y)</td><td>29%</td><td>Grade ≥ 3 CRS: 1%<br>Grade ≥ 3 NE: 15%<br>Early death: 8%<br>Death in remission: 0%</td></tr><tr><td>MDACC<sup>88</sup><br>(NCT03263572)</td><td>Induction/conso: Blina 28 d<br>+ Pona daily<br>(x5 42d cycles)<br>Maint: Pona 5y</td><td>60</td><td>55 (20-83)</td><td>CR/CRi: 97%<br>MRD-negative<br>(IG/TR):<br>98%</td><td>91% (3y)</td><td>12%</td><td>Grade ≥ 3 CRS: 0%<br>Grade ≥ 3 NE: 0%<br>Early death: 3%<br>Death in remission: 3%</td></tr><tr><td>GIMEMA<br>ALL2820 trial<sup>90</sup><br>(NCT04722848)</td><td>Induction: Pona<br>Conso: Blina<br>(x 2-5 cycles)</td><td>133</td><td>57 (20-87)</td><td>CR: 98%<br>MRD-negative:<br>(unspecified)<br>73%</td><td>92% (1,5y)</td><td>3%</td><td>Grade ≥ 3 CRS: 1%<br>Grade ≥ 3 NE: 1%<br>Early death: 3%<br>Death in remission: 3%</td></tr><tr><td>EWALL-PH03<br>(NCT04688983)</td><td>Randomisation:<br>- Ima + Chemo<br>- Pona + Chemo<br>- Pona + Blina</td><td>-</td><td>≥ 55 y</td><td></td><td>Stopped Results pending</td><td></td><td></td></tr></tbody></table>

**Abbreviations:** Blina = Blinatumomab, Chemo = chemotherapy, Conso = consolidation, CR = complete remission, CRi = Complete response with incomplete hematologic recovery, CRS = cytokine release syndrome, d = day, Dasa = Dasatinib, Ima = Imatinib, Maint = maintenance, IG/TR = immunoglobulin and T-cell receptor, MRD = measurable residual disease, NE = neurological events, Pona = Ponatinib, y = years.
CNS relapses have been observed with the chemo-free approach in Ph+ ALL. In the d-ALBA trial,⁸⁵ 4 of the 9 relapses occurred in the CNS. Similarly, 4 isolated CNS relapses were observed in the MDACC trial combining ponatinib and blinatumomab.⁸⁸ The 2 patients mentioned above who had received blinatumomab and inotuzumab ozogamicin relapsed in the CNS.⁹⁶ To prevent this progression, the number of chemotherapy-injected lumbar punctures should probably be increased, as is already done in the GIMEMA ALL2820 trial (NCT04722848) mentioned above and the extended MDACC trial (NCT03263572). This could be applied easily to older patients with the hope to reduce CNS relapse in this population.

Another issue with TKIs is the emergence of BCR::ABL1 mutations, especially the T315I mutation, which confer drug-resistance to first and second generation TKIs. This is particularly observed in patients presenting with IKZF1 deletion associated with PAX5 or CDKN2A/B mutations.¹⁰⁰ Ponatinib and new third-generation TKIs, such as olverembatinib,¹⁰¹ as well as asciminib, an orally BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (unlike other TKIs which target the ATP-binding site of BCR::ABL1), remain effective against mutations in the ATP-binding site that cause resistance to other TKIs. Dual BCR::ABL1 inhibition with asciminib and TKIs that target the ATP-binding site may also prevent the emergence of TKI-resistant clones¹⁰² and this strategy is already being tested (NCT03595917, recruiting).

## Anti-CD19 CAR-T Cells

KTE-X19 is approved for R/R adult B-ALL based on the ZUMA-3 study,⁶⁸ but only 8 patients over 65 and 15 Ph+ patients were treated in this trial, making its efficacy uncertain. A pilot study (NCT05707273) is currently enrolling patients aged over 55 years with a B-cell ALL, in order to receive CAR-T cells when achieving CR. Preliminary observations, presented at the ASH 2024 meeting,⁷¹ showed good safety and efficacy profiles in the first 13 treated patients, that included 5 with Ph+ ALL. The major issue remains long-term detectable persistence of the CAR T-cells, and the need for allo-HSCT in consolidation for long term remission, which may be a limitation in older patients, mostly ineligible for such procedure. However, with the very efficient combination of blinatumomab + TKI, the addition of CAR T-cells, as consolidation, may lead to very long-term survival in older patients with Ph+ ALL in the future.

In summary, the prognosis of older patients with Ph+ALL has drastically changed in recent years. The combination of blinatumomab and ponatinib will probably become the standard of care for these patients while the therapeutic armamentarium is growing and may help to enhance outcome in the future. However, attention still needs to be paid to prevent TKI mutations and CNS leukemia. The cardio-vascular complications of ponatinib as well as compliance on the long-term could be also a matter of concern in the elderly population.

## T-Cell ALL

T-cell ALL (T-ALL) accounts for around 25% of adult ALL and is a rare disease in the elderly. Again, the intensive pediatric-

inspired based regimens are very toxic for this population for whom age-adapted chemotherapy remains the gold standard.¹⁰³ No real breakthroughs have been obtained in this setting recently. Innovative drugs and/or targeted therapies, discussed below, are still being investigated but no new standard of care has been established, and prognosis is still very poor in this particular population, without any consensual guidelines.

## Nelarabine

Nelarabine is a second generation purine nucleoside analog and a prodrug of the deoxyguanosine analog ara-G. It is approved for R/R T-ALL. Nelarabine has not been used specifically in the older population, neither for R/R disease nor in front-line, meaning that its role is not established yet for this population.¹⁰⁴

## Anti-CD38 Monoclonal Antibodies

Immunotherapy for T-ALL is clearly not as developed as it is for B-ALL, as the difficulty is to find a suitable surface antigen to target. CD38 is currently the only target of interest, first because a majority of T-ALL express CD38¹⁰⁵ and secondly because 2 anti-CD38 monoclonal antibodies (daratumomab and isatuximab) are already available after being approved for the treatment of multiple myeloma. The combination of daratumumab¹⁰⁶,¹⁰⁷ or isatuximab¹⁰⁸ with chemotherapy has been reported in R/R T-ALL as part of phase II studies. So far, results are disappointing even if the toxicity profile is acceptable. Only few older patients have been treated, meaning that anti-CD38 therapeutic antibodies cannot be recommended so far in this population.

## CAR T-Cells

Other antigens, such as CD7 or CD5, represent also natural targets for T-ALL. If no anti-CD7 or CD5 monoclonal antibodies are available in the clinic, the recent advent of anti-CD7 or anti-CD5 CAR-T cells seems very promising, considering the impressive preliminary results reported in patients with R/R T-ALL.¹⁰⁹⁻¹¹² However, the fact that CD5 and CD7 are also expressed on the majority of normal T cells, some NK cells and CAR-T cells themselves, can be an obstacle to their efficacy by a phenomenon of fratricide killing and/or impaired expansion after infusion. The development of CAR-T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker is thus of crucial interest. The first results of such an approach are very encouraging.¹¹³ Again, no specific data nor experience are available with CAR-T cells for older patients with T-ALL so far.

## Venetoclax

As for Ph- B-ALL, targeting the anti-apoptotic protein BCL2 with venetoclax could also be an option in T-ALL of the elderly, however only few cases have been published. Venetoclax in monotherapy¹¹⁴ or in combination with chemotherapy⁶⁴,¹¹⁵ can be efficient in older patients with R/R T-ALL but no specific experience has been reported yet, especially in the front-line setting.

In summary, T-ALL remains an unmet medical need, especially in elderly patients. It is hoped to see rapidly the emergence of active drugs against T-ALL leukemic cells. Some targetable pathways are being investigated such as the IL-7R or JAK/STAT pathways.¹¹⁶,¹¹⁷
# Chemo-immunotherapy in ALL of elderly patients

Further options could be the new anti-CD38 monoclonal antibody MOR202<sup>118</sup> or targeting the CD99 tumor associated antigen, which is highly expressed on malignant T cells and much less on nonmalignant T cells<sup>119</sup>. It would also be interesting to propose personalized regimens based on the molecular profile of each patient and/or individualized in vitro drug screening strategies.<sup>27,120</sup>

## Conclusion and Perspectives

The treatment of older patients with ALL remains challenging. However, the future is promising and new strategies, including chemo-free regimens or low-dose chemotherapy combined to immunotherapy or targeted treatments, have already improved significantly the outcome of this particular high-risk population. Blinatumomab, inotuzumab ozogamicin and new-generation TKIs are becoming the drugs of choice for treating older/elderly patients with Ph- and Ph+ B-ALL while there is still an unmet medical need for treating those with a T-ALL.

## Disclosure

The authors declare no conflict of interest except:

PC: Advisory boards: Takeda, Servier, Abbvie, Priothera; International congresses: Abbvie, Research grant: Pfizer.

## CRediT authorship contribution statement

**Perrine Moyer:** Writing – review & editing, Writing – original draft. **Aude-Marie Fourmont:** Writing – review & editing, Writing – original draft. **Lucie Freiman:** Writing – review & editing, Writing – original draft. **Philippe Rousselot:** Writing – review & editing, Writing – original draft. **Patrice Chevallier:** Writing – review & editing, Writing – original draft.

## Acknowledgments

Medical writing for this manuscript was assisted by MPIYP (MC Béné), Paris, France.

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