Management of ALL in Adults: 2024 ELN Recommendations From A European Expert Panel

Special Report
Management of ALL in adults: 2024 ELN

recommendations from a European expert panel
Nicola Gökbuget,1 Nicolas Boissel,2 Sabina Chiaretti,3 Hervé Dombret,4 Michael Doubek,5 Adele Fielding,6 Robin Foà,3 Sebastian Giebel,7
Dieter Hoelzer,1 Mathilde Hunault,8 David I. Marks,9 Giovanni Martinelli,10 Oliver Ottmann,11 Anita Rijneveld,12 Philippe Rousselot,13
Josep Ribera,14 and Renato Bassan15
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1
Department of Medicine II, Hematology/Oncology, Goethe University, University Hospital, Frankfurt, Germany; 2 Hospital Saint-Louis, Assistance Publique–
ˇ
Hopitaux de Paris, Paris, France; 3 Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy; 4 Leukemia Department,
ˇ
University Hospital Saint-Louis, Assistance Publique–Hopitaux de Paris, Saint-Louis Research Institute, Université Paris Cité, Paris, France; 5 Department of Internal
Medicine–Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; 6 UCL Cancer Institute, London, United Kingdom; 7 Department of Bone
Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland; 8 Maladies du
Sang University Hospital of Angers, FHU Goal, INSERM, National Centre for Scientific Research, Angers, France; 9 University Hospitals Bristol NHS Foundation
Trust, Bristol, United Kingdom; 10 IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy; 11 Division of Cancer and Genetics, Cardiff
University School of Medicine, Cardiff, United Kingdom; 12 Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 13 Clinical Hematology Department,
Centre Hospitalier de Versailles, Université Paris-Saclay, Versailles, France; 14 Clinical Hematology Department, Institut Catala d’Oncologia Hospital Germans
Trias I Pujol, Josep Carreras Research Institute, Badalona, Spain; and 15 Division of Hematology, Ospedale dell’Angelo, Mestre-Venice, Italy
Experts from the European Leukemia Net (ELN) working covers treatment approaches, including the use of new
group for adult acute lymphoblastic leukemia have identi- immunotherapies, application of minimal residual disease
fied an unmet need for guidance regarding management for treatment decisions, management of specific sub-
of adult acute lymphoblastic leukemia (ALL) from diagnosis groups, and challenging treatment situations as well as late
to aftercare. The group has previously summarized their effects and supportive care. The recommendation pro-
recommendations regarding diagnostic approaches, vides guidance for physicians caring for adult patients with
prognostic factors, and assessment of ALL. The current ALL which has to be complemented by regional expertise
recommendation summarizes clinical management. It preferably provided by national academic study groups.
Introduction Methods
The European Working Group for Adult is part of the Euro- The panel includes 17 members representing national study
pean Leukemia Net (ELN) and was founded by representa- groups. Members met in person and defined topics, tables, and
tives of national academic multicenter study groups for adult responsibilities of coauthors (supplemental Table 1, available
on the Blood website). Coauthors performed literature searches
acute lymphoblastic leukemia (ALL) in Europe. The group has
of PubMed database and considered relevant abstracts. The
identified an unmet need for guidance regarding manage-
manuscript was reviewed by all coauthors. Formal corrections
ment of adult ALL from diagnosis to aftercare. A previous
were performed by the corresponding author. Disagreements
publication covered diagnostic approaches, prognostic
were summarized and discussed in the whole group. The group
factors and assessment of adult ALL.1 With increasing
agreed on the final version of the manuscript. Owing to rapid
complexity of therapeutic options there is also a need for
innovation and availability of new data, together with a lack of
guidance regarding clinical management. Standard therapy
randomized trials for many essential questions, most of the
with pediatric-based regimens is successful but requires
statements have an evidence level of “expert recommenda-
optimization. Also, treatment decisions based on minimal
tion” for clinical practice.
residual disease (MRD) require standards. Immunotherapy is
integrated to an increasing extent into first-line therapies,
whereas management of relapse is still a considerable chal- Induction and consolidation therapy in
lenge. Treatment approaches must be adapted to specific
subgroups, such as older patients or Ph/BCR::ABL1-positive Ph-negative ALL
ALL and practical management is challenging in specific sit- General principles
uations, such as secondary leukemia. Finally, the increasing The aim of intensive induction therapy is to obtain a complete
number of long-term survivors highlights the need for opti- remission (CR) in as many patients and as early, safely, and deep
mized aftercare and surveillance for late effects. Therefore, as possible. CR rate in adults aged between 15 to18 years and
the group decided to develop an ELN recommendation for 55 to 65 years with Ph/BCR::ABL1-negative (Ph-) ALL is ~90%.4
management of ALL as published for other entities.2,3 Approximately 5% display primary resistance after 2 cycles, and
9 MAY 2024 | VOLUME 143, NUMBER 19 1903

~5% die early of disease- or therapy-related complications. allergic reactions. Any premedication should only be adminis-
Treatment is usually risk-adapted using prognostic factors (PF) tered if drug monitoring can be offered. Otherwise, there is the
and course of MRD for treatment decisions regarding intensity risk to overlook inactivation of ASP.
of chemotherapy, use of immunotherapies, or indication for
stem cell transplantation (SCT). A comprehensive diagnostic The second induction or first consolidation consists usually of
characterization is the basis for optimal management as CP, cytarabine (AC) and mercaptopurine (MP) or HD-
described previously.1 methotrexate (MTX)/HD-AC.23 HD-AC/idarubicin can be used
as salvage.13 The few patients failing to enter CR after 2
induction courses have highly resistant ALL and are candidates
Pediatric-based chemotherapy in adult ALL
to alternative immunotherapies depending on the protocol.
In a meta-analysis 25 out of 27 reports clearly favored the
pediatric-based approach as standard of care (SoC).5 In patients
up to 45 to 55 years overall survival (OS) improved to an Consolidation
average of 60% (supplemental Table 2). Comparison of pedi- Consolidation is administered to patients in CR. Outcome is
atric-based regimens vs standard Hyper-CVAD led to similar best with rotational multidrug cycles consisting of HD-MTX and

conclusions in a monocentric trial.5 Pediatric-based therapy was HD-AC (also useful as CNS-penetrating agent), PEG-ASP and
particularly effective in standard risk ALL6-9 and patients with other drugs (supplemental Table 2). BFM (Berlin-Frankfurt-
negative MRD6,10-12 ensuring OS of ~70%.13-16 The typical Munster group)–based regimens include a delayed reinduction
compounds are corticosteroids (especially dexamethasone phase. The average duration of consolidation is ≥6 months, for
[Dexa]), vincristine, antimetabolites (6-thiopurines, cytarabine, 6 to 8 total courses. HD-AC, HD-MTX, etoposide, and CP were
and methotrexate) and asparaginase (ASP; pegylated or not) essential to improve outcome of high-risk subsets and T-ALL.
plus intensive supportive care, avoidance of inappropriate dose HD-AC (4-8 doses at 1-3 g/m2), PEG-ASP and HD-MTX (1-1.5 g/
reductions/delays and a risk-adapted SCT. m2, followed by folinic acid rescue) are administered in blocks.
Higher MTX dosages of 3 to 5 g/m2 are used especially for
Induction patients whio are at high risk and T-ALL. A randomized trial
demonstrated an improved outcome for patients receiving
For prephase, corticosteroids are usually administered for 5 to 7
consolidation MTX at 3 vs 0.5 g/m2, however the lower dose is
days; other drugs are occasionally added, for example, cyclo-
unusual.12 A phase 2 trial in adolescents and young adults (AYA)
phosphamide (CP) and intrathecal (IT) prophylaxis after sam-
used a lower MTX dose with weekly dose adaptions (Capizzi
pling of cerebrospinal fluid (CSF). First induction lasts ~4 weeks
style).6 Capizzi MTX showed in pediatric trials (up to age 30)
and carries the highest risk of complications, mandating for
outcome superior to MTX 5 g/m2 in T-ALL but not in B-ALL.24,25
intensive support, including granulocyte colony stimulating
factor (G-CSF), transfusions and optimal prophylaxis and man-
Given the heterogeneous consolidation protocols, the compa-
agement of infections. The induction backbone consists of
rable results after adjustment for patient age and risk class, and
vincristine, steroids, an anthracycline, and ASP. Dexa is highly
the lack of randomized comparisons, at present no single
active, including activity in the central nervous system (CNS),
regimen can be recommended as SoC for Ph-negative ALL.
but requires careful adaption of dose and schedule. If Dexa is
Pediatric-based regimens are favored. It is strongly recom-
administed over a prolonged period, an increasd risk of severe
mended to participate in (or adopt) prospective clinical trials.
infections has been observed. Therefore, shorter term applica-
Experience and established guidelines at the sites are impor-
tion with interruptions has been implemented by several groups
tant for adoption of distinct protocols.
during induction therapy. Early high-dose (HD) anthracyclines
worsen myelotoxicity and mucositis.17 A randomized trial failed
to demonstrate an advantage from increasing the CP dose Frontline targeted therapy of
upfront, however fractionated doses were of benefit to patients
aged >55 years receiving less intensive consolidation.13 Pegy- Ph-negative B-LIN ALL
lated asparaginase (PEG-ASP) provides a longer asparagine Because of the many opportunities offered by immunother-
depletion (serum enzymatic activity ≥0.1 IU/mL detectable for apies,26 modified regimens with targeting agents are tested to
14 to 30 days depending on dose) compared with the native increase response, OS, and if possible, to reduce the high
compound.5,14,15,18,19 Compared with native ASP, the drug toxicity burden because of intensive chemotherapy and SCT.
causes rarely severe allergic reactions in adults. ASP in general The identification of surface markers as target for immuno-
can cause coagulopathy, thrombosis, hyperglycemia, pancrea- therapies is therefore essential part of initial diagnosis.1 The
titis, and liver toxicity being more frequent and of greater compounds and mechanisms of action are discussed in
concern in adults than children.20,21 It is crucial to establish a “Relapsed/refractory ALL.”
specific schedule for toxicity monitoring and management20,21;
PEG-ASP schedule and dosing should be adapted to age, body Evidence is accumulating rapidly that immunotherapy can
mass index (higher toxicity if body mass index is >30 kg/m2) and improve antileukemic efficacy (Table 1). Anti-CD20 antibodies,
hepatosteatosis (higher toxicity if positive ultrasound scan)14,15 the bispecific CD19/CD3 antibody blinatumomab (Blina) and
and to the intended duration of activity. Any other potentially the CD22 antibody-drug conjugate inotuzumab ozogamicin
hepatotoxic drugs should not be administered during expected (InO) have been integrated into frontline and salvage regimens
ASP activity duration, with the exception of strict clinical indi- in clinical trials.
cation.18,22 More recently premedication before use of
PEG-ASP has been discussed to reduce the risk of infusion Approximately 40% of adult B-lineage (B-LIN) ALL express the
reactions which are sometimes difficult to differentiate from real CD20 antigen in >10% to 20% ALL blasts. Anti-CD20
1904 9 MAY 2024 | VOLUME 143, NUMBER 19 GÖKBUGET et al

ALL-ELN RECOMMENDATION PART 2
Table 1. Trials with upfront targeted or subset-specific therapy in adult Ph− ALL
Combination CRD/
Study (reference) ALL subset treatment Age (y) No. CR (%) RFS (%) OS (%) EFS (%) FUP Annotations

Rituximab/ofatumumab
(anti-CD20 antibody)
MDACC27 CD20+ B-ALL Hyper-CVAD + R ×8 in ≤60 68 100 70 75 — 3y Better outcome vs no R patients
cycles 1-4, ×4 in (P < .001 for CRD, P = .003 for
maintenance cycles 6, OS); outcome not improved by
18 R in patients aged 60+
GMALL28 CD20+ B-ALL GMALL 07/2003 + R ×8 15-55 117 94 64 75 — 3y Better outcome vs no R patients
(SR), ×3 (HR) in (P < .009 for CRD), with better/
induction/consolidation faster MRD clearing (MRD <
0.01% 60% at day 21)
GRAALL-200329 CD20+ B-ALL A: SOC 40 105 94 — 50 43 4y Better outcome vs no R patients
B: SOC + R ×16-18 during (24-53) 104 92 61 55 (P < .04 for EFS, P =. 02 for
induction/consolidation relapse incidence)
UKALL 1430 CD20+/− B-ALL A: SOC 25-65 288 92 — — 42 3y No overall benefit from R
(29% Ph+) B: SOC + R ×4 in induction 289 94 48 (P = .28), better outcome with R
after MAC SCT (EFS 72% vs
50%, P = .03)
MDACC31 CD20+/− B-ALL Hyper-CVAD + 41 (18-71) 46 CD20+ 93 — 66 61 4y CD20+: EFS and OS with R 43%
ofatumumab ×8 in 23 CD20− 70 65 (P = .119) and 48% (P = .123);
induction/consolidation CD20-: EFS and OS with R 50%
(P = .89) and 62% (P = .61)
Blinatumomab
GIMEMA LAL 231732 CD19+ B-ALL SOC + blinatumomab ×2 18-65 146 90 56-87 65-91 48-85 1.5 y 95% MRD negative after
in consolidation blinatumomab I (P = .001); OS
by age (P = .0009) and DFS/EFS
by Ph-like (P = .006) and MRD
(P = .0002)
GRAALL-2014- CD19+ B-ALL SOC + blinatumomab ×5 35 (18-60) 95 NR 69-90 92 — 1.5 y 74% MRD negative after
QUEST33 (high risk) in consolidation/ blinatumomab; DFS by high or
maintenance very high risk class (P = .018)
MDACC34 B-ALL Hyper-CVAD + 34 58 100 84 85 — 3y 76% and 95% MRD negative after
blinatumomomab ×2 (17-59) (20 with InO) cycle 1 and overall, resp.; no
after induction and/or relapse/death in InO-treated
x2-4 after group (OS 100%)
consolidation ± R/
ofatumumab (CD20+) ±
InO ×4 after
consolidation
A, B: study arms in randomized trials; CR, complete remission; CRD/RFS, CR duration/relapse-free survival; FUP, follow-up; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; GRAALL, Group for Research on Adult ALL; GMALL, German Multicenter
Group for Adult ALL; HOVON, Hemato-Oncology Foundation for Adults in The Netherlands; InO, inotuzumab ozogamicin; LBL, lymphoblastic lymphoma; MAC SCT, myeloablative conditioned SCT; MDACC, MD Anderson Cancer Center; NR, not reported; R,
rituximab; SOC, standard of care (chemotherapy).
1906
9 MAY 2024 | VOLUME 143, NUMBER 19

Table 1 (continued)
Combination CRD/
Study (reference) ALL subset treatment Age (y) No. CR (%) RFS (%) OS (%) EFS (%) FUP Annotations
MDACC35 B-ALL Hyper-CVAD 4 cycles (50% 37 (29-45) 38 100 73 81 — 3y Amended to Hyper-CVAD 2
dose reduction) + cycles (75% dose reduction) in
blinatumomab ×4 after HR patients; overall MRD
induction and ×3 after negativity 97%; OS 88% no HR
consolidation + R/ feature vs 76% any HR feature
ofatumumab (CD20+) in
induction/consolidation
HOVON36 CD19+ SOC + blinatumomab ×2 53 71 77 — 53 68 (Ph−) 2y 53% and 91% MRD negative after
B-ALL (37% (prephase and after (18-70) (Ph−) blinatumomab I and II, resp.;
Ph+) consolidation I) EFS and OS 71% and 73% in
patients ≤60 years
GMALL0837 CD19+ B-ALL Blinatumomab 1 cycle in 18-35 63 all CR/ — — 71 3y 55% molecular CR after
(MRD MRD positive patients MRD+ blinatumomab I; subsequent
positive) after consolidation I SCT indicated in all patients
ECOG-ACRIN CD19+ B-ALL A: SOC consolidation 51 (30-70) 112 81 — NR — 5y CR rate on all study patients (n =
(phase 3)38 (MRD B: SOC consolidation + 112 71.4 488); median OS arm B not
negative) blinatumomab x4 reached (NR, >70% at 5 years)
vs 71.4 months (P = .003)
Nelarabine (T-specific
nucleoside analog)
MDACC39 T-ALL/LBL Hyper-CVAD + nelarabine 30 (13-78) 81 NR — 57 52 5y OS non-ETP 63% vs ETP 32%
after course 8 (×2) or 5 (P < .001); non-ETP: OS
and 7 (×1 each) nelarabine 83% vs no
nelarabine 38% (P = .003)
UKALL 14 (Phase 3)40 T-ALL A: SOC 25-65 75 90 — 61 57 3y No benefit from single nelarabine
B: SOC + nelarabine ×1 69 87 65 61 course (3 doses), all P values not
after induction II significant
A, B: study arms in randomized trials; CR, complete remission; CRD/RFS, CR duration/relapse-free survival; FUP, follow-up; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; GRAALL, Group for Research on Adult ALL; GMALL, German Multicenter
Group for Adult ALL; HOVON, Hemato-Oncology Foundation for Adults in The Netherlands; InO, inotuzumab ozogamicin; LBL, lymphoblastic lymphoma; MAC SCT, myeloablative conditioned SCT; MDACC, MD Anderson Cancer Center; NR, not reported; R,
rituximab; SOC, standard of care (chemotherapy).
GÖKBUGET et al
antibodies were succesfully tested in de novo ALL.27,29 In a time of diagnosis. Some protocols recommend waiting until
randomized study, rituximab (Ritux) significantly decreased the peripheral blood (PB) blasts have been cleared or are reduced
relapse risk (RR), contributing to increase in the rate of SCT below a certain cutoff to prevent the risk of “seeding” the CNS
realization and improved OS.29 Interestingly, patients treated from a traumatic procedure. Postponing of lumbar puncture
with Ritux developed fewer allergic reactions to ASP; however, bears on the other hand the risk to not detect initial CNS
early MRD response was not improved. A randomized trial involvement which may be even more frequent in patients with
administering Ritux irrespective of CD20 expression failed to high white blood cell count (WBC). Factors predicting a higher
demonstrate a benefit30; however, in this study only 4 doses risk of initial CNS disease are T-ALL, high presenting WBC, and
were prescribed (vs at least 8 doses in other trials). high-risk cytogenetics, such as Ph+ ALL and t(4;11).1,47 MRD
detection in CSF has been attempted but is not part of standard
Preliminary data with Blina, partly in association with InO are management.
encouraging and confirm high rates of conversion to MRD
negativity, with low RR and an improved OS at limited follow-up All patients require CNS prophylaxis. Cranial irradiation, IT
between 1 and 4 years.32,33,35,37 A randomized trial with Blina chemotherapy, and components of systemic therapy which
consolidation added to a standard backbone for patients with cross the blood-brain barrier have all been used. Currently,

MRD negative ALL aged between 30 and 70 years indicates an cranial irradiation is rarely administered as prophylaxis. There
advantage for patients treated with Blina in terms of OS are insufficient data to clearly dissect the relative values of CNS
according to a preliminary analysis.38 Thus, there is increasing penetrating systemic therapy vs IT prophylaxis; therefore, both
evidence that Blina likely benefits in consolidation of patients are recommended although the critical component is most
with negative and positive MRD. likely the IT prophylaxis.
Overall, the use of Ritux is recommended for the management IT chemotherapy

of CD20+ ALL, for at least 8 doses. Similarly, because of the
MTX, ARAC, and steroids can all be safely administered IT, and
favorable early results and high expectations with upfront InO
all have been used, either singly or in combination with no clear
and Blina in CD22+ and CD19+ B-ALL, participation into InO
benefits to any specific IT regimen. IT medications should be
and Blina trials for untreated patients is recommended until
administered in sufficient volume to distribute well throughout
results from ongoing studies are available. The concurrent use
the CSF. An equivalent volume of CSF to the volume of drug is
of an anti-CD20 antibody in CD20+ ALL represents SoC as well
usually removed before administration and the CSF should
as the use of Blina in case of molecular failure.
always be sent for analysis. The patient should remain recum-
bent for at least 1 hour.48 It is a critical that conventional “cut-
ting” needles carry a high risk of hygroma49 and subdural
Maintenance therapy hemorrhage; therefore atraumatic needles are recom-
Maintenance therapy is strongly recommended in all patients.
mended.50 The ideal number of IT injections is undetermined,
Maintenance therapy was not tested in randomized trials but
but most protocols recommend 8 to 15 total doses. Close
any attempts to omit maintenance have resulted in inferior
attention must be paid to the supportive care, such as blood
outcomes.41,42 Insufficient maintenance therapy significantly
product support. In rare instances when lumbar punctures are
worsens OS.7,41 Long-term drug exposure is probably needed
difficult to perform an Ommaya reservoir can be considered as
to eradicate MRD.42
an individual alternative taking procedure related risks and
uncertainties regarding adequate dosing into account. Practical
MP and MTX are the main drugs in maintenance. Intermittent IT
aspects of IT treatment are reviewed by Olmos-Jimenez et al.51
prophylaxis is part of most regimens. Some groups include
other compounds, such as the POMP regimen (MP, MTX,
prednisone, and vincristine),7,13,41 whereas the benefit is Systemic chemotherapy
debated. In addition, data on a potential benefit of vincristine or Systemic chemotherapy may also help prevent CNS relapse.
steroid pulses in pediatric patients with ΔIKZF1 are controver- A meta-analysis of 43 trials showed a benefit to adding HD-
sial.43,44 The use of Dexa instead of prednisone in maintenance MTX in terms of reduction in RR and improved event-free
may lead to an increased incidence of infection-related survival (EFS), although only a small effect on CNS dis-
deaths.45 Therefore, maintenance without vincristine or ste- ease.52 A recent randomized trial showed a benefit in terms
roid pulses is preferred by most groups. A total treatment of disease-free survival (DFS) (but no impact on CNS relapse)
duration of 2 to 2.5 years including maintenance is recom- for 3 g/m2 over 0.5 g/m2 with no excess toxicity for the
mended. Intervals of ~3 months are suggested for MRD testing higher dose.53 Dexa may be superior to prednisolone in
during maintenance. reducing CNS RR.54
CNS-directed prophylaxis MRD-based treatment modification

CNS infiltration occurs in 5% to 10% of adults at diagnosis. It Given the paramount prognostic impact of MRD response,
can be classified as none (CNS-1), <5 white cells/μL (CNS-2), >5 most groups recommend therapy changes based on MRD. As
white cells/μL or a cranial nerve palsy (CNS-3) but pragmatically, described previously MRD based treatment decisions require
one should be suspicious if any blast cells are seen in the CSF.46 adequate and standardized methodology for MRD detection.1
It must be routinely ruled out and subsequently monitored by Important decision factors are time point and level of MRD,
analysis of cytospin preparations and/or multicolor flow- method, presence of other PFs, and suggested treatment
cytometry (MFC) analysis of CSF obtained at or soon after the modifications.37 Early good MRD response is associated with
ALL-ELN RECOMMENDATION PART 2 9 MAY 2024 | VOLUME 143, NUMBER 19 1907

favorable outcome. In one series 12% of patients at standard impact of MRD before SCT is correlated to the time-interval
risk showed no detectable MRD at day 11 of induction and had between MRD detection and transplant, the potential interim
an excellent prognosis.55 A later time point after first consoli- therapies, the conditioning regimens, and other transplant
dation was identified as most prognostically relevant for RR.56 related factors.
Thus, earlier time points are suitable to identify patients for
potential deescalation of therapy in clinical trials, whereas later It is recommended to change therapy in patients with persistent
time points are helpful to recognize candidates for treatment or recurrent MRD. Compounds with different mechanisms of
escalation. The most relevant time point depends on protocol. action compared with chemotherapy are potentially most
If it is the primary goal to identify patients with chemotherapy promising. To date, Blina is the only compound tested in a
resistance, all relevant chemotherapy compounds should have pivotal trial for MRD positive B-LIN ALL. Patients with an MRD
been administered before changes are made keeping in mind >0.1% were included either in first or later remission. The pri-
that MRD testing does not represent the extramedullary mary end point, achievement of a complete molecular remis-
compartment. In most protocols, the relevant time point will be sion (CMR) after 1 cycle, was achieved in 78%. Furthermore, a
~2 to 3 months from diagnosis. favorable median survival of 36.5 months was obtained and
patients achieving a CMR had a significant benefit. This treat-

It is also important to identify the most predictive level of MRD. ment was a bridge to SCT in 67% of the patients. The RR after
A threshold of 0.01% (ie, 10−4) is often considered because this SCT was low. However, OS was impaired by a treatment-related
is in line with the sensitivity of MRD assays. Each log-level mortality (TRM) >30% which is explained by the high median
increase of MRD is associated with shorter time to subsequent age (42 years), the high rate of full conditioning and mismatch
hematologic relapse.57 The median time to hematologic donors.67,68 On the other hand, most patients without subse-
relapse was 7.6 months vs 4.9 months for patients with MRD quent SCT relapsed and beyond complete molecular remission
>0.01% vs 0.1%, respectively.56 Patients with low-level MRD no factors predicting RR in patients without SCT were identified.
that is <0.01% may have an intermediate prognosis58,59 and In the future immunotherapies or other targeted drugs should
should be considered for MRD-based treatment interventions in be evaluated in the setting of MRD persistence or recurrence,
the future. not hematologic relapse only.
In addition, the method of MRD detection influences treatment Overall, patients with MRD >0.01% after 3 blocks of standard
decisions. Thus, quantitative polymerase chain reaction (PCR) therapy have an indication for SCT and for targeted therapies.
measurement of clonal immunoglobulin/T-cell receptor rear- To date, there is no evidence that treatment reduction, except
rangements (IG/TR) requires 4 to 6 weeks to set-up the appro- for omission of SCT, can be recommended outside of clinical
priate assay. MFC may deliver results more quickly but may yield trials in patients with favorable course of MRD. Whether SCT
uncertain results particularly in regenerating bone marrow (BM). can be omitted in all patients with molecular CR, including
Decisions based on the safe confirmation of negative MRD status those in specifically unfavourable subgroups should be inves-
require strict adherence to methodological prerequisites.1 This tigated.69 After conversion from MRD positive to MRD negative
requires MRD assessment in an experienced reference laboratory status using new compounds such as Blina, subsequent SCT
and a sensitivity of at least 0.01% for the time point which is remains the standard in younger patients with matched donor.
considered for the treatment decision. In older patients with high risk of TRM either dose-reduced
conditioning regimens or a consolidation or maintenance
Most trials on the prognostic impact of MRD were conducted in strategy should be followed.
newly diagnosed patients. In adult ALL limited data demon-
strate a correlation between persistent MRD after therapy with
new targeted compounds in the relapsed/refractory (R/R) SCT
setting60 but correlation is less stringent than that in first-line SCT is a complex multistep, multifactorial, and highly individ-
therapy. Nevertheless, MRD response to salvage therapy indi- ualized treatment concept. As such, it is considered an effective
cates the antileukemic efficacy of a defined approach and is treatment for preventing relapse, combining myeloablative
relevant for patients. doses of chemotherapy and/or radiotherapy with potential
beneficial graft-versus-leukemia reaction. Unfortunately, it is
Very few attempts for reduction of standard therapy have been also associated with significant incidence of TRM, reaching 13%
made so far. One randomized trial in pediatric patients who are after SCT from HLA-matched sibling donors (MSD) and 21% for
at standard risk with good MRD response evaluated the SCT from unrelated donors (URD).70 Haploidentical SCT with
outcome with a reduced reinduction regimen. This modification posttransplant CP is increasingly implemented in many coun-
was associated with an inferior DFS, particularly in children tries. Overall, indication for SCT is weighed against the reduc-
aged >10 years.61 Further clinical trials are warranted to tion of the RR and the risk of TRM. Despite attempts to
evaluate treatment reduction particulary in the era of elaborate prognostic scores, the potential benefit in many
immunotherapies. individual cases is uncertain.71 The role of autologous (auto)
SCT appears questionable and mainly affected by the MRD
Most groups build their indication for SCT on MRD. SCT pro- status.72 Results of recent SCT trials are summarized in Table 2.
vides a survival advantage for patients with poor MRD
response.56,62 However, the realization of SCT requires time Ph-negative ALL
and many patients relapse during this period despite continued Most prospective studies evaluating the role of SCT have been
chemotherapy.56 In addition, a high MRD level before SCT is conducted considering the availability of MSD. Patients in CR1
associated with a higher RR after SCT.63-66 The prognostic with MSD were offered SCT, whereas those lacking MSD were

Table 2. Results of SCT for adults with ALL (selected studies)
Study Population Donor N OS (%) LFS (%) RI (%) TRM (%)

73 −
Nishiwaki et al, 2013 Ph in CR1 MSD 388 65 (4 y) 62 (3 y) 25 (3 y) 13 (3 y)
URD 434 64 (4 y) 61 (3 y) 17 (3 y) 22 (3 y)
Cord blood 95 57 (4 y) 51 (3 y) 22 (3 y) 27 (3 y)
Ph− in CR > 1 MSD 89 47 (4 y) 48 (3 y) 31 (3 y) 21 (3 y)
URD 158 39 (4 y) 38 (3 y) 26 (3 y) 36 (3 y)
Cord blood 53 48 (4 y) 44 (3 y) 29 (3 y) 27 (3 y)
Giebel et al, 201670 Ph+ and Ph−, CR1 MSD 252 71 (2 y) 61 (2 y) 26 (2 y) 13 (2 y)

URD 310 67 (2 y) 60 (2 y) 19 (2 y) 21 (2 y)
74
Cahu et al, 2016 T-ALL in CR1 MSD+URD 414 54 (5 y) 51 (5 y) — —

T-ALL in CR2 93 37 (5 y) 33 (5 y) — —
T-ALL in CR > 2 or active disease 94 12 (5 y) 9 (5 y) — —
75 +
Brissot et al, 2015 Ph in CR1 MSD 234 45 (5 y) 36 (5 y) 43 (5 y) 20 (5 y)
URD 249 47 (5 y) 40 (5 y) 30 (5 y) 30 (5 y)
Giebel et al, 201876 Ph+ in molecular CR1 MSD 255 70 (2 y) 55 (2 y) 28 (2 y) 18 (2 y)

URD 247 69 (2 y) 60 (2 y) 19 (2 y) 22 (2 y)
Autologous 67 70 (2 y) 52 (2 y) 47 (2 y) 2 (2 y)
Pavlu et al, 201777 Ph+ and Ph−, primary induction failure* Various 86 23 (5 y) 17 (5 y) 54 (5 y) 29 (5 y)
78 + −
Santoro et al, 2020 Ph and Ph in CR1 Matched URD 809 62 (3 y) 53 (3 y) 28 (3 y) 19 (3 y)
Mismatched URD 289 62 (3 y) 55 (3 y) 25 (3 y) 20 (3 y)
Haploidentical† 136 54 (3 y) 49 (3 y) 28 (3 y) 23 (3 y)
79 + −
Nagler et al, 2021 Ph and Ph in CR1 or CR2 MSD 1891 67 (2 y) 55 (2 y) 32 (2 y) 13 (2 y)
Haploidentical† 413 59 (2 y) 51 (2 y) 26 (2 y) 23 (2 y)
Beelen et al, 202280 Ph−, HR, CR1, prospective trial MSD 176 59 (5 y) 56 (5 y) 23 (5 y) 21 (5 y)
URD 366 58 (5 y) 55 (5 y) 25(5 y) 20 (5 y)
Marks et al, 202281 Unfit for myeloablative conditioning, CR1 MSD/URD 249 55 (4 y) 47 (4 y) 34 (4 y) 20 (4 y)
MSD, matched sibling donor; RI, relapse incidence; URD, unrelated donor.
*No CR after at least 2 cycles of induction.
†Unmanipulated graft.
treated either with auto SCT or chemotherapy. Most of the trials reported.83 In MRD-negative older patients, SCT should not be
demonstrated a beneficial effect of MSD-SCT (reviewed by Bassan used outside prospective clinical trials. It is crucial to continue
et al4 and Hoelzer et al82). However, these studies were performed MRD monitoring after SCT to identify upcoming relapses.
before the era of routine assessment of MRD and with non–
pediatric-based comparator arms. Currently, MRD status is
Ph-positive ALL
considered the most important PF, driving SCT indication. In 2
subsequent trials 522 Ph-negative patients who are at high risk up SCT was associated with significant OS benefit in patients
to the age of 55 years were intended for SCT.62 Among these, treated with imatinib and chemotherapy84 and therefore remains
54% received a transplant in CR1 (MSD or URD). SCT was asso- SoC. Indications may be restricted with the introduction of third
ciated with longer leukemia-free survival (LFS) in patients with generation tyrosine-kinase inhibitors (TKI) or with consideration
postinduction MRD ≥10−3 but not in good MRD responders. This of specific PFs. This, however, requires verification in prospective
observation, however, may not necessarily apply to less intensive trials with sufficiently long follow-up. Clinical trials with third
chemotherapy protocols and a randomized trial assessing SCT generation TKI and immunotherapy in older patients may pro-
indication in MRD-negative patients who are high risk is ongoing.37 vide relevant data on long-term survival without SCT.
Strict MRD monitoring should be performed after SCT.85

Indications for SCT refer mainly to younger adults aged up to Selection of TKI or decision on TKI change in MRD-positive
55-60 years and vary among study groups.1,83 There is no patients should be based on ABL-kinase domain (KD) mutation
consensus regarding older patients. High variability in clinical status, level, and time of MRD reoccurrence. Patients with early
practice between study groups and individual centers has been MRD-negative status may either be treated prophylactically or

preemptively for at least 1 year of continuous molecular CR. specific AYA trials,101 or (3) the extension of upper age limit in
Both strategies have been documented feasible in a prospec- pediatric trials.10 Thereby outcome of AYA has improved
tive randomized trial.86 significantly (supplemental Table 2). Currently, there is no evi-
dence that AYA have poorer results with modern pediatric-
SCT procedure aspects based regimens compared with unmodified pediatric protocols.
Donor type choice does not differ from other leukemias. All ALL Any age cutoffs for defined protocols should be based on a
MSD, URD, or haploidentical donors may be considered. How- clear rationale.
ever, the choice of conditioning regimen may influence
outcome. A randomized trial in pediatric ALL showed a clear Ph-positive ALL Although most adult groups use dose-
benefit of myeloablative total body irradiation (TBI) (12 Gy)– reduced chemotherapy plus TKI but recommend SCT, pedia-
based conditioning over chemotherapy-based regimens mainly tricians have maintained intensive chemotherapy and reduced
because of reduced RR.87 In case of limited access to TBI or for SCT indications mostly based on early response including
patients who cannot tolerate this procedure, conditioning based MRD.102 Owing to the rarity of the disease in AYA, patients
on IV busulfan or HD thiotepa may be an alternative.88,89 Results should be included in prospective trials.

of prospective study in adults indicate noninferiority of busulfan/
CP compared with TBI at a total dose of 9 Gy plus CP.90 For Older patients (>55-65 years)
older patients reduced-intensity conditioning (RIC) should be Many groups set an upper age limit for unmodified pediatric-
considered preferably within clinical trials. The broadest experi- based protocols at the age of 55 years. This is supported by a
ence comes from a trial which offered conditioning with fludar- recent publication indicating a mortality in CR of ~35% in
abine, melphalan, and alemtuzumab.81 Nevertheless, the role of patients aged between 55 and 59 years and treated according
RIC SCT in older patients remains uncertain, particularly with the to an intensive pediatric-based protocol.13
availability of immunotherapies and third generation TKI.
Biologic and clinical features Older patients usually suffer
Antithymocyte globulin (ATG) as part of conditioning prevents from B-LIN ALL.103,104 The incidence of poor PFs, such as pro-B-
chronic graft-versus-host disease (GVHD) as confirmed by 2 ALL, including KMT2A-rearranged ALL, and early T-ALL
recent retrospective studies by the EBMT but was associated with increases with age.104,105 There is a high incidence of Ph+ALL
increased RR without significant impact on OS.91,92 G-CSF (24%-51%) or complex aberrations.103,106 Older patients’ per-
mobilized PB stem cells is the most frequently source of stem formance status frequently deteriorates quickly with the onset
cells.93 of disease and comorbidities are frequent. In one study the
incidence of any comorbidity assessed by the HCT-CI
(Hematopoietic Cell Transplantation Comorbidity Score) was
Treatment of specific subgroups 76%. Early death (ED) was significantly associated with comor-
Adolescents and young adults bidity.107 Furthermore, secondary ALL is more frequent in the
AYA with cancer have been recognized as a vulnerable popula- older population.108
tion in transition between childhood and adulthood aged
between 15 and 20 years. A definition of 15 to 39 years old was PFs Potential PFs for ED risk included comorbidity, age, and
used defining therapeutic strategies based on unmodified performance status before onset of leukemia.103,104 PFs for RR
pediatric protocols, whereas it is also recognized that patients are similar to those in younger patients. In older patients with
aged between 15 to 25 years are more exposed to psychosocial less intensive therapy, a higher rate of MRD persistence can be
issues.94 Currently, intensive pediatric-based protocols are used expected.104 Therefore, prospective evaluation of MRD is
up to the age of 55 to 65 years. The outcome of AYA is lower essential to identify those who could benefit from alternative,
than in children even within pediatric trials. Contributing factors experimental treatments.
include differences in disease biology, historically different
therapeutic approaches, and lack of inclusion in clinical trials. Management A prephase therapy can be essential particu-
Psychosocial issues may decrease adherence95 to long-lasting larly for stabilization of the general condition. Induction therapy
and complex protocols. Multidisciplinary teams aware of these is the most critical phase for management. ED has a wide range
complex situations should be involved in treating AYA with ALL. (0%-42%) (Table 3). The most frequent cause is infection
(reviewed by Gokbuget103). Even with an age adjusted
Biology in AYA The incidence of ALL is lower in AYA than in chemotherapy >95% of the patients experience grade 3 to 4
children or older adults. T-ALL and LBL are more frequent. hematologic toxicity during induction. The Swedish registry
Some molecular entities are identified more frequently in AYA, reported intensive care unit admission in 17% of the patients
such as iAMP21, IGH@ rearrangements, MEF2D rearrange- aged <55 years113 and ED was similar with intensive or so called
ments, or Ph-like ALL. palliative approaches.119
Ph-negative ALL Many historical comparisons addressed the Outcome Population-based studies reported CR rates of 40%
outcome of AYA concomitantly treated in pediatric studies or to 70% and OS of 6% to 30%.106,113,119,120 With protocols spe-
historic trials designed for adult ALL (reviewed by Boissel and cifically designed for older patients with ALL CR rates of 43% to
Baruchel96) and confirmed the advantage of pediatric strate- 90% and OS rates <30% to 40% after 5 years can be achieved
gies. These observations have led to different strategies in (Table 3). As in protocols for younger patients, steroids and
variable age groups including (1) the expansion of pediatric- vincristine are the most important drugs in induction therapy.
based protocols in adult patients,14,37,97-100 (2) the setting of One central question is whether anthracyclines must be included,

ALL-ELN RECOMMENDATION PART 2
Table 3. Results of chemotherapy and antibody therapy in older patients

Patients CR/CRi rate Early DFS/EFS
Study Year Age Ph+ (N) (%) death (%) Failure (%) CCR (%)* (%)* OS (%)†
Chemotherapy
Hunault-Berger et al109 2010
Arm 1 68 (55-77) No 31 90 7 3 32 (2 y) n.r. 35 (2 y)
Arm 2 66 (60-80) 29 72 10 17 52 (2 y) 24 (2 y)
Goekbuget et al110 2012 57 (55-85) No 268 76 14 10 32 (5 y) n.r. 23 (5 y)
Fathi et al111 2016 58 (51-72) Yes 30 67 3 30 n.r. 52 (2 y) 52 (2 y)
Ribera et al112 2016 66 (56-79) No 54 74 14 14 n.r. 24 (2 y)‡ 30 (2 y)‡
113,
Kozlowski et al § 2017 69 (62-82) Yes 35 71 20 9 n.r. n.r. 20 (3 y)
Kozlowski et al113,|| 2017 63 (55-79) Yes 79 89 13 n.r. n.r. n.r. 39 (3 y)
Goekbuget et al104 2022 68 (56-86) No 841 73 14 13 37 (3 y) n.r. 28 (5 y)
Cohort 1 593 72 15 13 32
Cohort 2 248 75 9 16 50
Chemo-Immunotherapy
Stelljes et al114 2022 64 (56-80) No 43 100 0 0 n.r. 73 (2 y) 81 (2 y)
InO chemo
Chevallier et al115 2022 68 (55-84) No 131 90 n.r. n.r. n.r. 50 (2 y) 54 (2 y)
InO chemo
Goekbuget et al116 2021 65 (56-76) No 34 83 7 10 n.r. 89 (1 y) 84 (1 y)
Chemo Blina
Advani et al117 2022 75 (66-84) No 29 66 n.r. n.r. n.r. 37 (3 y) 37 (3 y)
Blina mono
Nasnas et al118 2022 68 (60-87) No 80 99 0 0 n.r. n.r. 46 (5 y)
InO Blina chemo
Arm 1, continuous infusion doxorubicin; Arm 2, pegylated doxorubicin; Cohort 1, original version of protocol; Cohort 2, more dose density, PEG-ASP consolidation, MRD-based Blina; CCR, continuous complete remission; CRi, complete remission with
incomplete recovery; InO, inotuzumab ozogamicin; n.r., not reported; Ph+, Ph/BCR::ABL1 positive ALL included yes or no.
*Median months or probability.
†Probability.
‡Estimated from Kaplan-Meier curve.
§EWALL protocol.
||ABCVD protocol.
which type of anthracycline and which dose-intensity. Anthracy- trials.115,118 Particularly in patients aged >70 years with poor
clines contribute considerably to BM toxicity. One approach is risk cytogenetics, outcome was very poor.118
the use of idarubicin in induction based on a potentially lower
cardiac and hepatic toxicity. The results of liposomal anthracy- Although these combined approaches are of great interest and
clines in older adults with ALL are not convincing. Tolerability of bear promise for older patients, it will be a challenge to define
ASP is reduced in induction in older patients (reviewed by new standard regimens and demonstrate their benefit compared
Gokbuget103). One group reported an induction mortality of 34% with historical data which would be necessary to obtain not only
in patients aged 60 to 65 years treated with an intensive induc- marketing authorization of immunotherapies for first line but also
tion including Dexa, high doses of daunorubicin and 2 doses of reimbursement in different health care systems.
PEG-ASP.22 Overall, it is advisable to start ASP in older patients
later during consolidation. Ph/BCR::ABL1-positive (Ph+) ALL
Diagnosis and molecular features Clinical presentation
Although options for intensification of induction therapy are and diagnosis are comparable to Ph-negative ALL. Cardiovas-
limited, there is still space for intensification of consolidation cular assessment is particularly important because of the safety
therapy. To date the largest prospective trial was conducted by

profile of TKIs and attention to the echocardiography is relevant
the GMALL used a pediatric-based 2-phase induction followed as some TKI may cause QT prolongation. It is essential to
by alternating consolidation cycles and maintenance up to identify Ph+ ALL as early as possible.
2.5 years. In CD20 positive ALL 8 doses of Ritux were added.
The median age was 67 (55-85) years. The CR rate was 76% in Confirmation of Ph+ ALL relies on karyotyping and/or molecular
268 patients; ED rate was 14% and mortality in CR 6%. OS at 5 genetics.1 Additional chromosomal aberrations have been
years was 23%.110 Based on this protocol a consensus treatment linked to inferior outcome.124-126 PCR analysis of BCR::ABL1
approach for older patients with ALL was defined by the should not be the sole diagnostic test as atypical
EWALL. The Hyper-CVAD protocol was associated with a CR BCR::ABL1 transcripts may be missed, but determining the
rate of 88%, death in CR of 31%, and OS at 5 years of 21%.27 BCR::ABL1 isoform is important for subsequent MRD analysis.
With the most recent version of the GMALL protocol There is no unequivocal data on the prognostic relevance of the
including MRD-based immunotherapy a CR rate of 75%, ED of more frequent p190 isoform vs the p210 breakpoint present in
9%, and OS of 50% at 3 years was reported104 (Table 3). one-third of patients.
Overall, these standard regimens are the basis for further

improvement by moderate time and dose intensification in Principles of treatment TKIs induce CR in 90% to 95% of
consolidation, consideration of SCT with RIC and decision on patients, display low toxicity, and enable a greater proportion of
targeted therapies based on MRD. Immunotherapies such as patients to undergo SCT. TKI should be initiated as early as
Blina should be considered in older patients with B-LIN ALL possible, because delays during induction reduce their efficacy.
showing persistent MRD67; also patients with PR or failure after During induction it is possible to rely on a TKI only to achieve CR,
induction can benefit from treatement with InO or Blina. Older but in practice TKI are usually combined with steroids and often
patients may also benefit from the addition of Ritux to the vincristine. Simultaneous administration with most chemothera-
chemotherapy backbone. peutic agents is feasible. CNS-prophylaxis is mandatory.
Further improvement can be expected from complementing or Induction and postremission chemotherapy The com-
replacing chemotherapy with immunotherapy independent of bination of imatinib with nonintensive induction was prospectively
MRD. Older patients show a similar tolerability of Blina and InO studied, demonstrating a higher CR rate and lower induction
as younger patients.121,122 In the first experience with a com- mortality without compromising OS.84 Chemotherapy de-
bination of InO with dose reduced chemotherapy and Ritux in escalation during induction is applicable to all age groups but
patients aged >63 years a CR rate of 98% was reported in has not been universally adopted.127-129 Because a minority of
48 evaluable patients. Seventy-eight percent of the patients patients achieve a deep molecular response after TKI-only
achieved negative MRD status. However, despite the use of induction, additional antileukemic modalities are required as
dose-reduced chemotherapy, 93% of the patients developed postremission therapy130 (reviewed by Foa and Chiaretti131)
grade 3 to 5 infections, 17% increases of bilirubin or trans- (Table 3).
aminases and 81% had prolonged thrombocytopenias of
>6 weeks with grade 3 to 4 hemorrhage in 15%. Veno-occlusive Postremission therapy is commonly initiated with 1 or 2
disease/sinusoidal obstruction syndrome (VOD/SOS) was consolidation cycles combining a TKI with more intensive
observed in 8% of the cases. The mortality in CR was however chemotherapy, analogous to treatment of Ph-negative patients;
22% to 25% and the 3-year OS was 56%.123 Importantly, the use of ASP is discouraged by some groups.132 Depending on
dose of InO was adapted during the trial in a total of 5 steps and comorbidities, transplant risk, age, patient preference, and
in a further modification Blina was added in the latest cohort MRD level, further postremission therapy will then consist either
after 4 cycles of InO-based chemotherapy. of SCT, continued consolidation and maintenance therapy, or
switching to an alternative treatment if response is deemed
In older patients trials with different combinations of chemo- unsatisfactory. Consolidation is followed by maintenance with
therapy and sequential trials with Blina and chemotherapy are the initial or an alternative TKI, depending on tolerability and
ongoing and yielded promising interim results.114-118 Longer efficacy.133-135 Stopping the TKI in patients who did not
follow-up will be essential, but it is of interest that despite undergo transplant is discouraged, even in patients with pro-
reduced chemotherapy, the risk of TRM was quite high in some longed MRD-negativity.

MRD MRD monitoring for Ph+ ALL should rely on BCR::ABL1 Observation of several CNS relapses emphasizes the need for
measurement but complemented by 1 additional method.1 intensive CNS-directed prophylaxis. The role of SCT in this
setting remains to be established, because ~50% of the
patients received SCT based on investigators’ choice. Several
Kinase domain (KD) mutations Point mutations in the KD
ongoing trials are evaluating the combination of TKI with Blina
of BCR::ABL1 contribute to most relapses on TKI. Increasing
as first-line therapy for older patients with Ph+ ALL. Also, the
BCR::ABL1 transcripts should prompt mutational analysis136 as the
role of SCT may be defined in the context of ongoing ran-
type of mutation may inform which TKI to switch to. In most cases
domized trials (NCT06061094).
ponatinib will be the TKI of choice. Switching even to the most
appropriate TKI will rarely induce a prolonged response in case of
overt hematologic relapse. Next-generation sequencing with a CNS prophylaxis Dasatinib crosses the blood-brain bar-
sensitivity of 1% to 5% is the method of choice to detect evolving rier,148 but the clinical relevance of CSF penetration of TKI is not
mutated clones in the MRD setting.136 The clinical relevance of well-described. Therefore, prophylaxis of CNS relapses is an
low-level mutations at diagnosis remains unclear.135,137 essential part of all TKI based regimens and usually relies on
intensive and prolonged application of IT prophylaxis.

Selecting TKI Published studies with long-term data indicate
that RD and OS with regimens combining chemotherapy and Salvage therapy Other than TKI, the modalities are the
either imatinib or second-generation TKI is comparable138 same as for other B-LIN ALL; most patients will have developed
which may in part be attributable to SCT as a confounding KD mutations. Second- and third-generation TKI have response
factor. In contrast, a randomized study in pediatric patients rates of 16% to 46%149,150 with OS of 6 to 9 months.147 OS is
showed superiority of dasatinib over imatinib when combined poor even in patients referred for SCT.151 With InO in R/R Ph+
with intensive chemotherapy.139 One caveat of this trial is ALL higher response rates, longer PFS, and a higher rate of SCT
however, the imatinib dosing, which was lower than typically compared with SoC were observed but no benefit in OS.122,152
prescribed for pediatric ALL. Treatment strategies that do not Single-agent Blina induced CR/CRh in 36% of R/R Ph+ ALL,
rely on SCT or combination with intensive chemotherapy may including patients with the T315I mutation.153 Median relapse-
benefit from second and third generation TKI. Thus, first-line free survival (RFS) and OS were 6.7 months and 7.1 months,
ponatinib combined with hyper-CVAD resulted in high CR respectively. Concurrent use of Blina and ponatinib in R/R Ph+
and molecular CR rates, and the 5-year OS (71%) was superior ALL resulted in a remarkably high CR rate (96%) and encour-
to historical controls.140 In a phase 2 trial of ponatinib plus aging OS (median 20 months), with acceptable tolerability.154
standard induction and consolidation chemotherapy in patients Optimal positioning of chimeric antigen receptor (CAR) T-cell
with newly diagnosed Ph+ ALL, the 3-year EFS and OS rates therapy in the treatment of Ph+ ALL remains to be determined.
were 70% and 96%, respectively141 (Table 4). Preliminary data Avoiding relapse is paramount because salvage therapies
of a randomized trial with ponatinib vs imatinib in combination remain unsatisfactory. In addition to immunotherapies, BH3-
with dose-reduced chemotherapy in 245 patients showed that inhibitors, and the novel allosteric kinase inhibitor ABL001
ponatinib yielded a significantly higher MRD response rate (asciminib) are of interest; both have a favorable toxicity profile
(34% vs 17%), whereas OS data were not different.146 and act synergistically with available therapeutic modalities
used in Ph+ ALL.
Dosing considerations apply to all TKI; for imatinib maintaining
a high initial dose (800 mg per day for 6-8 weeks) has been Ph-like ALL
associated with better outcome.128 Ponatinib (45 mg per day) Approximately 10% to 30% of cases with B-LIN ALL are char-
and nilotinib have been linked to cardiovascular adverse events, acterized by a gene expression profile similar to that of Ph+ ALL,
lowering the ponatinib dose when CR is reached to 30 mg per and they were therefore named BCR::ABL1-like or Ph-like ALL.
day reduces the risk of arterial occlusive events without
compromising efficacy.127 Doses <15 mg per day ponatinib are Diagnosis Ph-like ALL was first described in adult ALL.155,156
discouraged by pharmacokinetic data.127,147 Rigorous attention One signature in pediatric ALL, named BCR::ABL1-like, was
to normalization of blood pressure, blood glucose, and lipids is based on hierarchical clustering of 110 gene probe sets.157
essential. Other comorbidities to be considered include pul- Another signature with 257 gene probe sets, named Ph-like,
monary disease (dasatinib) and diabetes (nilotinib). Nilotinib was based on the prediction analysis of microarrays (PAM) clas-
and ponatinib may cause clinically symptomatic pancreatitis, sifier.158 A comparison of both classifiers found a relatively small
particularly in patients with a history of pancreatitis. Selecting degree of overlapping, with only 18% of patients consistently
TKI for first-line therapy depends on treatment regimen, classified. However, both classifiers identified patients with a
comorbidities, and drug approval in different health care poor outcome and tyrosine kinase fusion genes.159 Only 9 probe
systems. sets overlapped between the 2 lists, most likely because of
different approaches, algorithms, and patient demographics.
Immunotherapy Combining TKI with immunotherapy may
enhance antileukemic activity. Whether addition of Ritux The identification of Ph-like ALL remains challenging and is not
enhances efficacy as in Ph-negative ALL has not been estab- SoC. A 15-gene LFS (LDA) gene expression card can be used in
lished. Blina was shown to be highly effective in postremission clinical diagnostics using quantitative RT-PCR coupled with a
therapy combined with dasatinib.142 In this trial, all but 1 patient mathematical algorithm. The LDA card includes gene probes for
(98%) achieved a CR after dasatinib, and up to 60% obtained the most frequent tyrosine kinase genomic lesions in Ph-like ALL.
molecular response measured by BCR::ABL1 MRD after 2 cycles The concordance rate between the LDA card and the PAM
of Blina. At 18 months median follow-up, DFS was 88%. method is 87%.160 Another approach is the “BCR::ABL1-like

1914

Table 4. Prospective trials of 2nd and 3rd generation TKI as front-line therapy for Ph+ ALL
Molecular Allogeneic
TKI Reference N Age Treatment CR rate (%) response (%) SCT rate (%) RFS/EFS (%) Survival (%)
Dasatinib
70 mg BID Foa et al, 2011130 53 54 Prednisone 15 (d 85) 42 22 (20 mo) 31 (20 mo)
(24-77)
50 mg BID/100 mg QD Ravandi et al, 72 55 Hyper-CVAD 96 65 17 44 (5 y) 46 (5 y)
100 mg QD-70 mg QD 2015134 (21-80)
50 mg BID/100 mg QD Ravandi et al, 97 44 Hyper-CVAD 88 — 42 62 (3 y) 69 (3 y)
70 mg QD 2016129 (20-60)
140 mg QD; Rousselot et al, 71 69 EWALL backbone 24 10 28 (5 y) 36 (5 y)
>70 y: 100 mg QD 2016135 (55-83)
140 mg QD Foà et al, 2020142 63 54 Corticosteroids 98 60 (2 cycles of 38 88 (18 mo med. 95 (18 mo
(24-82) blinatumomab FU) med. FU)
Nilotinib
400 mg BID Kim et al, 2015143 90 47 Intensive chemotherapy 91 77 (3 mo) 63 72 (2 y) 72 (2 y)
(17-71)
400 mg BID Ottmann et al, 72 66 EWALL backbone 94 58 <0.01 33 42 (4 y) 47 (4 y)
2018144 (55-85)
Ponatinib
45-30-15 mg QD Jabbour et al, 76 47 (39-61) Hyper-CVAD 98 83 20 67 (5 y) 71 (5 y)
2018127
30-15 mg QD Ribera et al 30 49 (19-59) Intensive chemotherapy 100 71 at week 16 87 70 (3 y) 96 (3 y)
2022141 alone
45-30-15 QD Martinelli et al, 44 66.5 90.9 at week 47.7 at week 6 11 (transplant 48 (3 y) 58 (3 y)
2022145 6, 86.4 at 40.9 at month 6 unplanned)
month 6
BID, twice a day; FU, follow-up; med., median; QD, once a day.
GÖKBUGET et al
predictor,” based on the real-time quantitative–PCR quantifica- T-ALL
tion of 9 specifically overexpressed genes.161 For comparability of T-ALL comprises 25% of adult ALL171 and treatment is similar to
clinical trials the method for identification of Ph-like ALL should that for B-LIN ALL. After standard induction, an intensification
be clearly described. There is increasing evidence that BCR::ABL- phase containing CP and AC is usual. Intensive use of ASP was
like ALL should be identified as a subgroup in all patients. highly effective in pediatric T-ALL.172 It is not clear whether
nelarabine as consolidation improves outcome in adults. When
Molecular characterization Genomic screens and next- combined with the hyper-CVAD protocol in newly diagnosed
generation sequencing have revealed a highly diverse range adults with T-ALL/LBL, there was no OS benefit with the addition
of aberrations; these include many new fusion genes, including of nelarabine compared with the historical data.173 A randomized
ABL1-class and JAK-class fusion genes.162 Ph-like ALL aberra- pediatric trial has evaluated nelarabine in newly diagnosed T-
tions can be grouped in 5 major subclasses (supplemental ALL/LBL.174 In this study, the 5-year DFS was 88% in the nelar-
Table 3). Because most studies were carried out in children abine group vs 82% in the no-nelarabine group, with an
and young adults, the type of genomic lesions in older adults acceptable toxicity. The benefit of nelarabine was not observed
are less well-understood and might differ. in OS. Of note, the rate of isolated and combined CNS relapses
was reduced in patients treated with nelarabine. In adult ALL a

recent trial did not show a benefit of one course of nelarabine
Incidence The incidence of Ph-like ALL differs by geographic instead of induction phase 2.40 The GMALL 08/2013 trial added
region, age, reference group, and the methods used for iden- 2 cycles of nelarabine in standard-risk ALL and reported excellent
tification. With the PAM-classifier the incidence of Ph-like cases outcome; the exact role of nelarabine in this intensive pediatric-
in US cohorts was 20% to 24% in adolescents and older adults based regimen remains to be defined. On the other hand,
(>39 years old), with a higher incidence of 28% in younger nelarabine had limited efficacy in MRD positive immature T-
adults (aged 21-39 years)161 (Table 5). It is essential to note ALL175 (Table 1). The MDACC reported improved OS for patients
whether incidences refer to B-LIN as a whole or to a group treated with nelarabine compared with retrospective controls,
named B-other, that is, those without distinct cyctogenetic or with the notable exception of ETP ALL which did poorly.39 All
molecular aberrations. trials in adults did not reveal specific safety concerns. It is rec-
ommended to participate in nelarabine-based trials whenever
MRD response and prognostic significance Adults with possible and until more robust data are available.
Ph-like ALL had higher rates of MRD positivity after induction.
This was associated with an inferior EFS and OS. Seventy As for B-LIN ALL MRD testing is of utmost importance and
percent of patients with Ph-like ALL remained MRD positive.165 provides guidance for SCT indication. ETP ALL appears to have
This was confirmed in other adult populations.166,167 Data on a poor prognosis with chemotherapy and unfavourable onco-
the impact of MRD response in Ph-like ALL are conflicting. The genetics should also lead to consideration of SCT indication.
high RR does not always correlate with MRD response.32 On the Older patients with high-risk T-ALL may benefit from a RIC if
other hand, pediatric patients with Ph-like ALL and negative they have a well-matched donor.81
MRD status after standard treatment had no inferior
outcome.168 Therefore, aiming at MRD negativity retains LBL
prognostic importance also in this subgroup. Lymphoblastic lymphoma (LBL) is a rare entity of 1% to 3% NHL.
Eighty percent to 90% are T-cell (T-LBL). LBL and ALL are
separated by an arbitrary cut-point of 25% BM infiltration. Gene
Treatment Novel immunotherapies, such as Blina and InO
expression profile and single nucleotid polymorphism profiling
are investigated32,140,169 and appear to be effective according
revealed differences between T-ALL and T-LBL.176 T-LBL shows
to anectodal reports of successful treatment. Most groups rely
a prevalence of 70% of thymic subtype with a favourable
on an MRD-based approach and would offer SCT and/or tar-
outcome compared with 18% early T and 9% mature T-type.
geted therapy because of poor MRD response. There are no
studies confirming that SCT overcomes the higher RR in this
subgroup. Patient characteristics and PF T-LBL has a male pre-
dominance, presents most often with advanced stage III to IV,
Given the genetic heterogeneity in Ph-like ALL, translation of and 90% of patients with T-LBL have a mediastinal bulky mass,
this subtype to a useful treatment algorithm is a challenge. sometimes with concomitant pleural and pericardial effusions.
The ABL class fusions, usually identified by fluorescence in CNS involvement is seen in 5% to 10%, lymph node or other
situ hybridization were sensitive to SRC/ABL TKIs, such as organ involvement in 70%, and mostly LDH values are
imatinib and dasatinib, and there are several anecdotal clin- increased. In contrast to T-ALL, PB values are most often
ical reports.170 JAK2 fusions, EPOR rearrangements, and normal. There are no accepted adverse PFs. They differ in
activating JAK-STAT mutations were highly sensitive to the various trials, such as increased LDH, CNS involvement, and in
JAK2 inhibitor, ruxolitinib in preclinical studies. Another one study a gene classifier was prognostic.177
approach could be the use of ponatinib.161,170 For clinical
practice, identification of ABL-fusions and MRD-based treat- Therapy Rarely, tumor lysis syndrome and, in some cases,
ment modifications are essential and several groups recom- thoracic compression require immediate therapeutic interven-
mend identifying Ph-like ALL as a whole subgroup. tion by corticosteroids. Treatment should be based on ALL
Diagnostic methods require standardization, but the upfront regimens.177,178 The CR rate in most studies is 70% to 90%, the
identification offers the opportunity to further analyze out- EFS is 60% to 70% at 5 years, and the OS range is also between
comes of this subgroup. 60% and 70%. CNS prophylaxis is administered as in ALL.

Table 5. Results in adult Ph-like ALL
Total patients and frequency 5-year survival

Study Age group (y) of Ph-like ALL in B-other* (EFS or OS)
Roberts et al, 2014162 16-20 77 (21%) EFS 41%, OS 66%
21-39 46 (27%) EFS 24%, OS 26%
Herold et al, 2014163 16-20 5 (19%)

21-39 12 (18%) DFS (all ages) 19%
40-55 4 (9%) OS (all ages) 22%
55-84 5 (7%)
159
Boer et al, 2015 16-20 6 (25%) EFS (all ages) 24%
21-39 9 (19%) OS (all ages) 30%

40-71 6 (11%)
164
Jain et al, 2017 15-39 33 (42%)
40-84 16 (24%) OS (all ages) 23%
Roberts et al, 2017165 21-39 96 (28%) EFS 24%

40-59 62 (20%) EFS 21%
60-86 36 (24%) EFS 8%
Chiaretti et al, 2018161 0-15 2 (9%) EFS (excluding children) 22%

15-35 29 (29%) OS (excluding children) 37%
35 23 (31%)
Stock et al, 20196 17-39 41 (31%) OS (3 y), 63%

166
Chiaretti et al, 2021 18-65 28 (32%) EFS (2 y), 34%
OS (2 y), 40%
*B-other: Ph negative without other defining molecular abnormalities (eg, KMT2A, low hypodiploid, hyperdiploid).
In earlier studies despite mediastinal irradiation of 24-36Gy for reported 3-year OS of only 10%.185 Predictors for outcomes
residual tumors, the mediastinal relapse rate was high.178 This is include age, duration of first remission, response to initial salvage
now compensated by more intensive systemic chemotherapy. therapy, and ability to undergo SCT. For patients who are candi-
Positron emission tomography may theoretically guide therapy dates for salvage therapy, the choice of regimens will be based on
of residual disease179; however, the exact timing, the predictive the patient age and comorbidities, disease characteristics (eg,
role, and treatment consequences after positive positron immunophenotype, genetic characteristics, and extramedullary
emission tomography are not established. MRD in the BM or PB involvement among others), type of prior therapy (including SCT),
may help to evaluate the response similar to ALL. SCT has and duration of prior remission. R/R ALL is an emergency and
obtained equal results of an OS of 70% compared with patients should be referred to experienced centers to establish a
chemotherapy alone; the known selection bias for SCT must be comprehensive management plan since sequencing and timing of
considered, however. SCT is therefore reserved for patients salvage therapies are essential for outcome. SCT indication should
with T-LBL in second CR or refractory cases.175,177 be considered in all patients with R/R ALL.
Treatment of extramedullary relapses

Relapsed/refractory ALL CNS is the most frequent site of extramedullary relapse. CNS-
Conventional chemotherapy salvage directed treatment followed by combined systemic therapy is
Depending on protocol and subtype, 5% to 10% of patients will warranted.186 Recurrences within the CNS usually coincide with
be primary refractory, and an additional 30% to 60% of patients or predict systemic relapse; immediate MRD testing is therefore
will relapse. Although BM is the most frequent site of relapse, recommended. Although rapid improvement in neurological
extramedullary relapses can occur, and incidence may even symptoms and signs can often be achieved with intravenous or
increase with more widespread use of immunotherapies. Adult oral Dexa, IT therapy should be started promptly twice per
patients with R/R ALL have a poor prognosis with salvage che- week until the CSF is negative. Systemic reinduction therapy
motherapies. A new CR is attained in 20% to 40% of patients should include drugs able to cross the blood-brain barrier, such
depending on treatment line, but these remissions are in general as HD-MTX or -AC. Patients with isolated or combined CNS
not durable despite subsequent SCT. Prolonged DFS and cure are relapse are candidates for SCT. Although there are no data to
observed in ~10% to 15%113,180-185 (supplemental Table 4). An support any conditioning regimen in these circumstances, TBI
international study of 1706 patients with R/R Ph− B-LIN ALL regimens are preferred. A cranial boost of 6 Gy has been shown

to be tolerable in adults receiving TBI-based conditioning.187 recommended to administer only up to 2 cycles InO before
There are no randomized data on the potential benefit or SCT, to avoid double alkylators in conditioning and to strinctly
harms of giving additional IT therapy posttransplant, and the monitor patients for VOD signs after SCT. InO retains effec-
practice varies by institution. MRD testing in the CSF may help tiveness also in patient with high proliferative relapse205 and
to guide management. Regarding immunotherapies, elimina- shows some efficacy in extramedullary relapse.206 A close sur-
tion of CNS leukemia has been observed in patients treated veillance of liver function tests is advised.
with CD19 CAR T cells. Treatment of other extramedullary
relapses is rather individualized, depending on location. Usu- Blinatumomab Blina is a bispecific T-cell engager antibody
ally, chemotherapy or local therapies, for example, irradiation construct that enables autologous CD3-positive T cells to target
are attempted because the efficacy of immunotherapies is not and eliminate CD19-positive B cells including B-LIN blasts.
clear in this stetting. Blina has been approved for R/R ALL based on a randomized
study. The CR/CRi rate was 44% after Blina vs 25% after stan-
dard salvage chemotherapy.192 MRD negativity was 76% in the
New chemotherapeutic and targeted drugs
Blina group vs 48% in the control group and median OS was 7.7
Liposomal vincristine was developed with the goal of increasing
vs 4.4 months, respectively. The gain was more marked in

drug exposure of vincristine to leukemic cells while minimizing
patients receiving Blina as first salvage therapy and in patients
dose-limiting neurotoxicity. The overall response rate was (CR,
with BM infiltration <50%.207 AE of interest were manageable
CRi, and PR) was 32% with a median RD of 23 weeks and
cytokine release syndrome (CRS) and transient neurologic
median OS of 4.6 months.188 Grades 3 to 4 neuropathy
events. More favorable results with Blina were observed in
occurred in 25% of patients.
MRD-positive ALL as discussed above. Two recent pediatric
randomized studies have also investigated the use of Blina as
Clofarabine, a nucleoside analogue approved for use in chil-
postreinduction therapy in first relapse in an MRD setting and as
dren with R/R ALL, has as single agent a response rate of only
bridge to transplant.193,194 These studies demonstrated fewer
12% in adults. Response to combination regimens (etoposide/
and less severe toxicities, higher rates of MRD response, greater
mitoxantrone, cyclophosphamide, or cytarabine) have ranged
likelihood of proceeding SCT and improved DFS and OS in the
from 17% to 36%189 but the toxicity of these regimens is high,
Blina arm.
precluding the use of subsequent SCT in most patients.
Chimeric antigen receptor T-cells (CAR-T) CAR-T tar-
Nelarabine was approved for R/R T-ALL/LBL. The first study
geting the CD19 antigen have generated promising results in
showed a CR rate of 23% in 26 adult patients with R/R disease.
children and adults with R/R ALL. Characteristics and results of
A larger phase 2 study including 126 heavily pretreated R/R
largest noncomparative CAR-T studies published to date are
adult patients (ages 18-81 years) showed a CR rate of 36% and a
detailed in Table 6.195-203 Median ages were relatively low.
PR rate of 10%, with 80% of CR patients bridged to SCT.190
Overall response rates ranged from 67% to 97% in patients who
Significant neurologic toxicities are observed in ~10%. It is
were infused, and complete MRD response by MFC was ach-
not clear whether combination therapies yield higher responses
ieved in most responders. Most patients had very advanced
and with the increasing use of nelarabine in first-line therapy,
disease with a substantial proportion of patients relapsing after
the options in R/R ALL are more limited.
prior SCT. In order to make results comparable to other
approaches in R/R ALL the evaluation of intent-to-treat pop-
Immunotherapies ulations is essential, because not all patients receive an inten-
Antigens expressed on the surface of ALL cells (CD19, CD20, ded CAR-T-cell therapy owing to relapse or death during
CD22, and CD52) have proven to be appropriate targets for bridging or toxicities. Overall applicability of the procedure has
monoclonal antibodies (MoAb), used either alone or in combi- been evaluated in the mainly pediatric ELIANA trial, in which 75
nation with chemotherapy. MoAb and CAR T cells have thus of the 92 patients (81%) screened were infused.199 The rationale
been developed, demonstrating high antileukemic activity for an upper age-limit of 25 years in this trial is unclear. It led to
essentially when targeting the B-lineage CD19 and CD22 sur- the approval of tisagenlecleucel for patients aged between 1
face antigens (Table 6). Data for first line have been already and 25 years old with R/R ALL.
discussed. Antigen targeting is more difficult to develop in T-
ALL patients, even if the potential of targeting CD38, CD3, Data in adult ALL are still limited and data from clinical trials and
CD5, CD7, CD1a, and CCR9 is currently investigated. real-world indicate that the treatment principle is less effective
in full cytologic relapse. The Zuma-3 trial yielded promising
Inotuzumab InO is an anti-CD22 antibody conjugated to results in 55 patients with heavily pretreated adult R/R ALL and
calicheamicin, a cytotoxic antibiotic agent. InO has been a median age of 40 (28-52) years. Overall, 71 patients were
approved for R/R CD22-positive ALL based on a randomized enrolled. 62% of the treated patients had BM infiltration >25%
study, the rate of CR/CRi was 81% after InO vs 33% after at time of infusion. The CR/CRi rate was 71% in the patients who
standard salvage chemotherapy122 Among responders, the rate received infucion and 54% of all patients. The median OS of
of MRD negativity was 78% in the InO group vs 28% in the patients who received treatment was 18 months and the
control group. Median OS was 7.7 vs 6.7 months, respectively. median RFS 11.6 months. This trial led to marketing authori-
Liver-related adverse events (AE) were more common in the InO zation of brexucabtagene autoleucel.203
group, with an 11% incidence of VOD vs 1%, respectively.
Results were confirmed in long-term follow-up.204 It is open CRS and neurotoxicity are more common and more severe with
whether combination of InO and chemotherapy can further CAR-T as compared with Blina, likely because of massive,
improve outcome of R/R ALL. To reduce the VOD risk, it is induced CAR-T expansion/activation and endothelial activation.208

Table 6. Immunotherapy studies in R/R BCP-ALL
1918
OS
Median age Prior Molecular Bridge to estimate
Reference Study Eligibility Patients, N (y) alloHSCT ORR response alloHSCT or median

Multicenter antibody-
based studies
Kantarjian et al, 2016122 INO phase 3 (INO-VATE) ≥18 years R/R CD22+ ALL 109 47 16% 81% 63% 40% 7.7 mo
(67% salvage 1)
Topp et al, 2015191 Blinatumomab phase 2 ≥18 years Ph-neg R/R ALL 189 36 34% 43% 35% 40% 6.1 months
CR1 <12 months (61% salvage 1)
Kantarjian et al, 2017192 Blinatomomab phase 3 ≥18 years Ph-neg R/R ALL CR1 271 37 35% 44% 36% 14% 7.7 months
(TOWER) <12 months (42% salvage 1)
Gokbuget et al, 201867 Blinatumomab phase 2 ≥18 years ALL in HCR MRD ≥ 116 45 NR NR 80% 67% 36.5 months
(BLAST) 0.1% (65% CR1) complete MRD
response
Brown et al, 2021193 Blinatumomab COG 1-30 years HR/IR ALL in first 105 9 NR NR 79% 73% 79%
AALL1331 relapse (all salvage 1) at 24 months
Patients
Median OS
Coactivation age, y ORR CRS Neurotoxicity estimate
Reference Institution domain Screened, N (range) Infused, N % incidence, % incidence, % or median
CART19 studies
Maude et al, 2014195 Penn 4-1BB NR 14 30 90% 100% 43% 78%
(5-60) (severe, 27%) at 6 months
Davila et al, 2014196 MSKCC CD28 NR 50 16 88% 44% 25% NR
(NA) (severe) (Gr 3/4)
Lee et al, 2015197 NCI CD28 NR 15 21 67% 76% 19% 52%
(5-27) (Gr 3/4, 29%) (Gr 3/4, 5%) at 12 months
Turtle et al, 2016198 FHCRC 4-1BB 32 40 30 97% 83% 50% NR
(20-73) (Gr 3/4, 50%)
Gardner et al, 2017199 SCRI 4-1BB 45 12 43 93% 93% 44% 69.5%
(1-25) (severe, 23%) (severe, 21%) at 12 months
Maude et al, 2018200 Multicentre 4-1BB 92 11 75 81% 77% 40% 76%
(3-23) (Gr 3/4, 13%) at 12 months
Park et al, 2018201 MSKCC CD28 83 44 53 83% 85% 48% Median,
(23-74) (Gr 3/4, 26%) (Gr 3/4, 42%) 12.5 months
Hay et al, 2019202 FHCRC 4-1BB 59 39 53 85% NR NR Median,
(20-76) 20 months in MRD-
neg pts
Shah et al, 2021203
GÖKBUGET et al
Multicentre CD28 71 44 55 71% 89% 60% Median 18.2

(30–59) (Gr3/4 24%) (Gr3/4/5 26%) months
FHCRC, Fred Hutchinson Cancer Research Center; HCR, hematologic CR; HR, high risk; IR, intermediate risk; MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute; NR, not reported; ORR, overall response rate; SCRI, Seattle
Children’s Research Institute.
This makes CAR-T a therapy that should be administered in China in 20 patients has made major progress with high efficacy
specialized centers with a trained intensive care unit. Many and acceptable toxicity.217
issues still need to be elucidated, including the impact of CAR-T
subsets and persistence and the role of prior alloSCT and dis-
ease burden at infusion time on CAR-T efficacy and the need for
subsequent SCT. Genetically engineered “off-the-shelf” allo-
Late effects
geneic CAR-T, aiming to increase the applicability and rapidity With improving cure rates in adult ALL, research in late effects,
of the procedure, are under clinical development. Owing to a quality of life, and prognostic factors for late AE becomes
relatively high incidence of CD19-negative ALL recurrence, increasingly important. Survivors of childhood cancer have a
strategies combining CD19 and CD22 targeting, using dual or higher mortality, more chronic medical conditions, impaired
bispecific CAR-T, are also investigated. general and mental health, functional impairment, and poorer
social parameters compared to healthy relatives and the gen-
eral population.218,219 The GMALL group has recently summa-
In countries with all options available, the selection and
rized medical conditions in 538 long-term survivors of ALL
sequencing of Blina, InO, and CAR-T in R/R BLIN ALL is
therapy. Sixty-six percent of the patients had no comorbidity.
debated. There is no clear recommendation, because no

The most frequent diagnoses were infections (12%), fatigue
comparative studies have been conducted to date; further-
(13%), and GVHD (15%), whereas the most frequently affected
more, the availability of CAR T cells is limited. One might
organs classes were endocrine (17% men and 24% women),
propose favoring Blina in patients with relatively low disease
neurologic (27%), and skin (18%).220 Late effects can include
burden and preserved T-cell functions, whereas InO might be
general sexual hormone deficiency, thyroid disorders, prema-
used to reduce high disease burden though trials were limited
ture menopause, infertility, osteonecrosis and osteoporosis,
to patients with peripheral blasts <10 000/μL. A sequence of
cardiotoxicities, neuropsychological disorders, fatigue, and
both compounds, InO followed by Blina is also of interest. CAR-
second malignancies. The incidence of late effects is higher in
T might be indicated to treat more advanced disease, particu-
patients with SCT compared with those without and additional
larly recurrence after SCT. Even if CAR-T have been used as a
late effects, such as skin disorders in the context of chronic
bridge-to-transplant in most patients treated to date, the
GVHD, sicca syndrome, restrictive and obstructive pulmonary
question of whether CAR-T could replace SCT in the next future
disorders and cataract may occur.220,221 Although patients can
is of great clinical interest. The potential negative impact of
maintain their fertility after chemotherapy,222 infertility is
Blina209 or InO failure before CAR-T infusion requires larger
observed in almost all transplanted patients.223,224
evaluation. It remains unclear whether prior failure is a selection
of unfavorable disease biology or whether there is a specific
underlying mechanism. Avascular osteonecrosis is a clinically relevant problem which is
particularly observed in AYA. Intensified treatment with steroids
is a risk factor. Effects may be enhanced by asparaginase or HD-
Other investigational drugs MTX. In one pediatric study with postinduction Dexa or pred-
The most promising targeted agents are those targeting major nisone pulses the incidence of skeletal toxicity was overall 13%
molecular pathways controlling cell proliferation and apoptotic (11% fractures and 4% osteonecrosis). It was higher (25% vs
response (eg, multiple kinases and members of BCL-2, TP53, 11%) in older children (>10 years vs <10 years) treated with
RAS, mTOR/PI3K, pre-B/B-cell receptor, and NOTCH net- Dexa pulses.225,226 In contrast the UKALL/ECOG2993 study for
works).26 A variety of precision medicine approaches are under adult ALL found an overall incidence of 4% osteonecrosis. The
investigation though often based on considerations of disease incidence was higher in younger (<20 years) vs older
biology and anecdotal cases only.210 Further investigation in patients.227 Approximately half of pediatric patients with
prospective clinical trials remains a challenge. Some anecdotal osteonecrosis underwent surgical procedures.228 There might
remissions have been reported using FLT3 inhibitors, JAK be a correlation between coagulation disturbances and osteo-
inhibitors in activated IL7R pathway cases, imatinib or dasatinib necrosis. A PAI-1 gene polymorphism, which has been previ-
in NUP214-ABL1 mutated cases. More recently, promising data ously associated with risk of thrombosis was also associated
for menin inhibitors have been reported for KMT2a rearranged with osteonecrosis in childhood ALL.229 Recently a potential
acute leukemias. Targeted therapy is less developed in T- correlation between hypertriglyceridemia—a side effect of
ALL.211 The CD38 antigen has been considered as a potential ASP—and osteonecrosis has been reported.230 Most cases of
target in T-ALL. Combining targeting of CD38 with conventional osteonecrosis in patients with ALL occur within the first 3 years
relapse therapy has been explored.212,213 Targeting apoptotic of treatment and hip and knees are the most frequent locations.
pathways with BCL-2 inhibitors are currently tested in clinical The most sensitive diagnostic method is magnetic resonance
trials. Thus a selective BCL-2 inhibitor, with low-dose navitoclax, imaging (MRI). Some authors suggest performing at least 1
a BCL-XL/BCL-2 inhibitor was evaluated in 47 patients with regular MRI of hip and knees in high-risk populations at the end
relapsed T- and B-cell disease and achieved a remarkable 60% of therapy. Early detection, prevention, and management of
CR rate with 28% proceeding to potentially curative therapy.214 osteonecrosis is a major joint challenge for pediatric and adult
Frequent activation of the NOTCH pathway in T-ALL/LBL, hematologists.231
through NOTCH1 or FBXW7 gene mutations, led to developing
NOTCH targeting approaches, such as γ-secretase inhibitors Cardiotoxicity, particularly cardiomyopathy, pericarditis, or
(GSIs) or NOTCH inhibiting antibodies.215 Several groups are congestive heart failure, is often attributed to anthracyclines.232
attempting to develop CAR-T cells for relapsed T-cell disease The risk seems to be correlated with the overall drug dose,
that avoid the problem of fratricide and prolonged T-cell apla- although it may also be idiosyncratic and occur after few
sia.216 A first-in-man trial of donor-derived CAR T cells from applications. Factors, such as mediastinal irradiation, infections,

or combination of different cardiotoxic drugs may enhance the foetal survival and be performed in the setting of adequate
risk.232 Cardioprotection with dexroxazone may be an option, maternal hematopoiesis.
for example, in patients with higher cumulative doses of
anthracyclines.233 Cardiotoxicity, for example manifested as a MPAL
reduced ejection fraction may become manifest years after Leukemias of ambiguous lineage origin present a problem for
treatment. Cardiovascular check-up should, therefore, be part both diagnosis and management (reviewed by Gökbuget et al,1
of aftercare. Gokbuget et al,220 and Khan et al.240 In pediatric mixed
phenotype acute leukemias (MPAL) initial treatment with ALL-
Unspecific neuropsychological disorders are often described in oriented regimens is recommended.241,242 Lack of response
adult patients with ALL.220 This includes complaints about should prompt a switch to AML-orientated regimens. A similar
cognitive disturbances. For this phenomenon, known as strategy for adults is reasonable. It is debated whether the
“chemo-brain,” a physiological correlate is unknown.234 A diagnosis of MPAL represents an indication for SCT in CR1 in
relevant number of cured patients with ALL suffer from general or only in cases of persistent MRD.
fatigue.220,235 Fatigue is probably underdiagnosed in after-
care236; its detection, for example, by specific questionnaires

Secondary ALL
should be attempted.
ALL arising as a second malignancy (with or without cytotoxic
therapy for a prior malignancy) is increasingly recognized
Survivors of ALL have an additional risk to develop cancer. PFs (reviewed by Aldoss et al243). Secondary ALL occurs after a
for secondary malignancies may be alkylating agents, epi- variety of antecedent diagnosis including breast cancer, lym-
podophyllotoxins, CNS irradiation, TBI conditioning before phomas, myeloma, sarcomas, and neuroblastoma. Cases in
SCT, and moreover different gene aberrations.237 In adult ALL which there has been no prior cytotoxic therapy, inherited
survivors the most frequent second malignancies are hemato- germ line mutations in tumor suppressor genes or oncogenes
poietic neoplasias which mostly occur within the first 5 to 10 such as TP53 (Li-Fraumeni syndrome) or mismatched repair
years after end of chemotherapy.238 In addition, a variety of genes (MSH2, MLH1, MSH6, and PMS2) should be sus-
solid tumors is observed such as breast, thyroid, gastrointes- pected.244 For ALL after prior cytotoxic therapy, US SEER reg-
tinal, lung, skin, urogenital, brain, or sarcoma.182 istry data showed a median latency of 60 months and a
significantly inferior median 5-year survival compared with de
It is very important to provide all physicians involved in aftercare novo ALL.245 Development of ALL after therapy with lenalido-
with sufficient information about treatment and the relevant mide may represent a specific biologic correlation.246 Gener-
aspects of after-care. Long-term observation of cured patients ally, treatment strategy is similar to newly diagnosed ALL
with ALL is an essential part of ongoing and future clinical trials although a higher risk of toxicity might be expected.
and a major challenge in an environment of limited financial
ressources for academic groups. Depending on the different ALL and Down syndrome
health care systems joint forces in dedicated late effect clinics Individuals with Down syndrome (DS) have a 10- to 20-fold
can combine pediatric and adult hematology teams. increased risk of ALL, which usually occurs during childhood and
is associated with a genetic susceptibility. ALL correlated to DS is
well-described for pediatric patients. Recently 3 distinct molecular
Management of specific situations subtypes with higher incidence in DS-ALL have been described
ALL in pregnancy (CRLF2 rearranged, C/EBP alteration, and IGH::IGF2BP1 rear-
Acute leukemia is estimated to affect 2 in 100 000 pregnancies. rangement).247 Pediatric patients with DS-ALL have an increased
Current treatments are typically chosen based on case reports RR and TRM, mainly because of infections. Although standard
and retrospective analyses and depend heavily on personal and therapies are usually offered to patients with DS-ALL, some
societal considerations as well as the medical considerations of modifications are recommended, such as reduction of anthracy-
gestational age, disease biology and the patient’s clinical sta- clines and high-dose methotrexate. Intensive prophylaxis and
tus. A comparison of 15 women treated during pregnancy to monitoring for infections is essential. Replacement of toxic che-
330 nonpregnant controls provided evidence that pregnancy motherapies by immunotherapies is tested in clinical trials. DS-ALL
does not necessarily affect the overall outcome of ALL.239 in adults should be managed accordingly.248
Pregnant women with ALL should always be managed in
experienced centers with close cooperation with the obstetric
and foetal medicine teams. The management depends on the
Supportive care
trimester of pregnancy. During the first trimester, termination of Supportive care recommendations of the EWALL have been
pregnancy is a strong consideration because foetal safety pre- published.249 In the following paragraphs, only selected spe-
cludes delivering of standard ALL therapy. Subsequently, many cific aspects for management of ALL are reviewed.
chemotherapy agents can be safely administered to achieve
maternal CR although systemic antifolates should be avoided at High WBC
any time during pregnancy. The potential use of ASP later When patients present with very high WBC, leukostasis with
during pregnancy is debated, particularly because of its effects resultant tissue damage can occur in vulnerable capillary
on coagulation and depending on risk-benefit ratio it should regions, causing organ compromise. Leukostasis is diagnosed
rather be postponed to treatment cycles after delivery. The use on the presence of unexplained hypoxia, neurological symp-
of specific steroids for fetal lung maturation should be consid- toms, renal failure, cardiac ischemia, priapism, or severe
ered. Delivery should be timed for the date consistent with retinopathy. Management of “symptomatic” leukostasis is a

medical emergency. It may be treated with leukapheresis, but because of conflicting data on their effect on the risk of ovarial
this should not be seen as a substitute for prompt initiation of insufficiency and likelihood of later pregnancy. Patients should
ALL therapy, such as steroid prephase. have the opportunity for counseling on the different available
options and GnRHa may be used based on individual consider-
TLS ations.258 It is recommended to reevaluate ovarian function after
Patients with a high risk of developing tumor lysis syndrome completion of chemotherapy (AMH, antral follicular count).
(TLS) (WBC >100 × 109/L, high tumor burden)250 should receive
increased hydration (3 L/m2 per day), unless there is evidence
of renal insufficiency and oliguria and rasburicase prophylaxis. Summary and outlook
Urinary alkalinization is no longer recommended.250 The basis for adequate management of ALL is the application of
Intractable fluid overload, hyperkalemia, hyperuricemia, comprehensive diagnostic tools, the identification of prognostic
hyperphosphatemia, or hypocalcemia are indications for renal factors including the continous monitoring of MRD.1 The standard
dialysis. treatment of ALL is often defined by national study groups and
international consortia259 as part of prospective treatment opti-
mization trial. Furthermore, the clinical data bases of study groups

Antiinfection prophylaxis
often include comprehensive data on biologic markers and are
Antibacterial, antifungal, and antiviral prophylaxis and active
sources of reliable real-world data.
management of infections are of utmost importance, given the
fact that infections are still the major cause of death in CR.
Currently, excellent results are achieved with current standard
Management should be performed according to respective
pediatric-based chemotherapy particularly in younger patients.
guidelines.
To reduce the burden of morbidity and mortality, less toxic
regiments are an important goal. The gap between health care
Growth factors
systems is increasing. Although many new compounds can be
The prophylactic administration of G-CSF in ALL shortened
used in first-line based on integration into NCCN guidelines in
neutropenia duration,251-254 improved adherence to chemo-
the United States,260 specific marketing authorization and
therapy schedule and in one study reduced the incidence of
reimbursement decisions are required in most European
infections.252 Based on these data the majority of European
countries.
study groups have implemented prophylactic use of G-CSF in
their pediatric-based protocols since decades. A joint analysis
Immunotherapy with antibodies is standard for R/R ALL. Avail-
of long-term follow-up data from 5 European clinical trials
ability of CAR-T as well as data in adult ALL are still limited and
revealed survival advantages in the G-CSF group, particularly in
the sequencing of these therapies will be a challenge. The
DFS (5-y DFS 38% vs 24%) and OS in T-ALL (5-y 51% vs 29%),
indication for CAR-T in relapse after SCT is generally accepted,
probably as the result of improved dose-dense administration
if possible, already in the setting of MRD relapse. In R/R ALL the
of chemotherapy courses without significant decrease of the 8
definition of adequate bridging therapies and the criteria to
weeks mortality rate.255
decide on the need of subsequent (second) SCT are essential.
Menstruation prophylaxis For Ph+ ALL, the selection of TKIs, the efficacy of chemotherapy-
To suppress menorrhagia during thrombocytopenic periods free regimens, indications for change of TKI, the impact of MRD
and avoid undesired pregnancy during chemotherapy, contin- measured with different methods, and the role of immunother-
uous administration of progestational agents is preferred over apies and HSCT will be important research questions.
combined oral contraception, especially during ASP treatment
period and its prothrombotic state. For norethisterone a Less progress has been made regarding prognostic classifica-
nonsignificant association between exposure to higher doses tion of T-ALL, and there are few promising new compounds.261
and risk of thromboembolism has been described; medroxy- Although overall prognosis of T-ALL is quite favorable, new
progesterone acetate was discussed as preferable option in approaches are urgently required for poor prognostic sub-
patients with high risk of venous embolism.256 Progestational groups because survival after relapse is rare.
agents should not be used >6 months to prevent meningioma
occurrence that has been reported lately. Late effects of treatment, such as osteonecrosis are increasingly
relevant with improved ALL survival, requiring joint efforts of
Preservation of fertility pediatric and adult study groups to better understand biology,
As part of informed consent before ALL therapy, hematologists improve surveillance and define potential treatment modifications.
should address the possibility of infertility in patients treated
during their reproductive years, discuss fertility preservation Many new treatment approaches are applicable only in small
options, and refer all patients to appropriate reproductive spe- subcohorts of ALL and represent a challenge for successful
cialists. Sperm cryopreservation should be proposed in all men clinical trials. This applies also for the need of more individu-
before start of chemotherapy. In women, ovarian tissue cryo- alized relapse therapies integrating molecular and immune
preservation is an option to be considered before SCT. To limit targets as well as in vitro response data. These strategies
the risk for disease reintroduction after ovarian tissue trans- require international collaboration including joint forces of
plantation, quantification of ovarian MRD is being explored to pediatric and adult study groups.
decide for ovarian reimplantation.257 So far there is no clear
recommendation for the use of gonadotropin-releasing hormone Regulatory prerequisites are expanding regarding marketing
(GnRH) agonists (GnRHa) for fertility preservation, particularly authorization and reimbursement for new drugs in ALL, which is

treated with complex combination therapies. The evaluation of Jazz Pharma, Novartis, Pfizer, Servier and research grants from Amgen,
new compounds in rare molecular subgroups of ALL will require Novartis, Incyte, Jazz Pharma, and Sanofi. S.C. served on the advisory
boards of Incyte, Pfizer, and AbbVie and as a consultant for Gilead and
European-level collaboration with the European Medical
Amgen. H.D. received research funding from Amgen, Astellas, Celgene,
Agency and intergroup data sharing, as in the Harmony IMI Incyte, Jazz, Pfizer, and Servier and honoraria from Daiichi Sankyo, Incyte,
initiative (https://www.harmony-alliance.eu). New strategies for Jazz, and Servier. M.D. received research support from AstraZeneca. R.F.
clinical trial design must be developed in concertation with received speaker honoraria from Amgen, Novartis, and AstraZeneca and
patient representatives, and there is an urgent need to support served on the advisory board of Merck Sharp & Dohme. S.G. received
speaker honoraria or served on the advisory boards of Amgen, Novartis,
and maintain the successful infrastructure of independent aca- Pfizer, Gilead, and Zentiva; received speaker honoraria from Angelini; and
demic study groups through funding programs.259 received travel grants from Gilead. M.H. received research support from
Novartis, travel support from AbbVie and Beigene, and speaker honoraria
In the next years, these challenges will become evident for the from Servier; joined the advisory board of Servier; and was part of advisory
boards of Amgen and Clinigen. D.I.M. provided consulting for Pfizer,
integration of new monoclonal antibodies and cell therapies
Novartis, and Kite. O.O. received speaker honoraria from, joined advisory
into first line. Several clinical trials are ongoing in Europe and boards of, and received research grants from Incyte; received research
worldwide requiring harmonization to enable future meta-ana- support from Amgen and Celgene; and received honoraria for advisory
lyses.57,185,262 First-line therapies will not address the impact of boards from Autolus. A.R. received research support from Servier. P.R.

received research grants from Pfizer and Incyte. J.R. received speaker
a single compound but on new combination strategies, risk
honoraria from and served on the advisory boards of Amgen, Pfiizer, Shire,
stratifications and approaches, such as SCT. One major research Ariad, Incyte, and Takeda and received research support from Amgen. R.B.
question will certainly focus on the future role of SCT in adult served on the advisory boards of Novartis and Kite/Gilead and received
and pediatric ALL. honoraria or travel support from Amgen, Incyte, Servier, Jazz, and Pfizer.
The remaining authors declare no competing financial interests.
Future ALL treatment will be based on very successful standards

ORCID profiles: N.G., 0000-0003-2291-8245; N.B., 0000-0003-2091-
with increasing implementation of immunotherapies. The goal 7927; M.D., 0000-0002-1269-6282; A.F., 0000-0002-4746-7789; S.G.,
is to improve the prognosis of patients who are at high risk but 0000-0002-4827-4401; M.H., 0000-0001-7777-5216; J.R., 0000-0003-
also significantly reduce treatment-related morbidity and mor- 1042-6024; R.B., 0000-0001-8214-2894.
tality for patients of all ages.
Correspondence: Nicola Gökbuget, University Hospital, Department of
Medicine II, Theodor Stern Kai 7, 60590 Frankfurt, Germany; email:
[email protected].
Authorship
Contribution: All coauthors reviewed literature, wrote parts of the
manuscript, reviewed the manuscript, and approved the final manuscript.
Footnotes
Conflict-of-interest disclosure: N.G. has received institutional research Submitted 19 December 2023; accepted 21 January 2024; prepub-
funding from Amgen, Clinigen, Incyte, Jazz, Novartis, Pfizer and Servier lished online on Blood First Edition 2 February 2024. https://doi.org/
and received speaker honoraria or fees for advisory board participation 10.1182/blood.2023023568.
from Amgen, AstraZeneca, Autolus, Celgene, Clinigen, Gilead, Incyte Jazz,
Novartis, Pfizer, and Servier. N.B. received honoraria from Amgen, Incyte, The online version of this article contains a data supplement.
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Management of ALL in Adults: 2024 ELN Recommendations From A European Expert Panel

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Special Report

Management of ALL in adults: 2024 ELN

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9 MAY 2024 | VOLUME 143, NUMBER 19 1903

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Overall, the use of Ritux is recommended for the management IT chemotherapy

CNS-directed prophylaxis MRD-based treatment modiﬁcation

ALL-ELN RECOMMENDATION PART 2 9 MAY 2024 | VOLUME 143, NUMBER 19 1907

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Study Population Donor N OS (%) LFS (%) RI (%) TRM (%)

Giebel et al, 201670 Ph+ and Ph−, CR1 MSD 252 71 (2 y) 61 (2 y) 26 (2 y) 13 (2 y)

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Giebel et al, 201876 Ph+ in molecular CR1 MSD 255 70 (2 y) 55 (2 y) 28 (2 y) 18 (2 y)

Strict MRD monitoring should be performed after SCT.85

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Table 3. Results of chemotherapy and antibody therapy in older patients

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Overall, these standard regimens are the basis for further

1912 9 MAY 2024 | VOLUME 143, NUMBER 19 GÖKBUGET et al

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Total patients and frequency 5-year survival

Herold et al, 2014163 16-20 5 (19%)

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Roberts et al, 2017165 21-39 96 (28%) EFS 24%

Chiaretti et al, 2018161 0-15 2 (9%) EFS (excluding children) 22%

Stock et al, 20196 17-39 41 (31%) OS (3 y), 63%

Treatment of extramedullary relapses

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Multicentre CD28 71 44 55 71% 89% 60% Median 18.2

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Future ALL treatment will be based on very successful standards

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