HEMATOLOGIC MALIGNANCIES

Recent Advances in Managing Acute

Lymphoblastic Leukemia
Daniel J. DeAngelo, MD, PhD1; Elias Jabbour, MD2; and Anjali Advani, MD3
overview

Acute lymphoblastic leukemia (ALL) is characterized by chromosomal translocations and somatic mutations
that lead to leukemogenesis. The incorporation of pediatric-type regimens has improved survival in young
adults, and the incorporation of tyrosine kinase inhibitors for patients with Philadelphia chromosome–positive
disease has led to further improvements in outcomes. However, older patients often have poor-risk biology and
reduced tolerance to chemotherapy, leading to lower remission rates and overall survival. Regardless of age,
patients with relapsed or refractory ALL have extremely poor outcomes. The advent of next-generation se-
quencing has facilitated the revolution in understanding the genetics of ALL. New genetic risk stratification
together with the ability to measure minimal residual disease, leukemic blasts left behind after cytotoxic
chemotherapy, has led to better tools to guide postremission approaches—that is, consolidation chemo-
therapy or allogeneic stem cell transplantation. In this article, we discuss the evolving and complex genetic
landscape of ALL and the emerging therapeutic options for patients with relapsed/refractory ALL and older
patients with ALL.

INTRODUCTION Regardless of age, relapsed disease is an insur-

ALL is a rare disease, with 5,930 new cases diagnosed
in the United States in 2019 (0.3% of all cancers).1 ALL
is increasingly recognized as a genetically heteroge-
neous disease, and a flurry of new genetic subtypes has
led to a refinement in risk stratification. Although most
cases of ALL are diagnosed in the pediatric population,
the incidence follows a bimodal pattern, with the first
peak occurring in children younger than age 5 and
a second peak occurring at approximately age 50.2
Measurement of minimal residual disease (MRD) has
led to prompt risk-adapted interventions and improved
outcomes.3,4 Tremendous progress has been made in
the treatment of children with ALL, with complete re-
mission (CR) rates of 95% and estimated 5-year event-
free survival (EFS) rates of 80% to 85%.5-7 Unfortunately,
the results for adult patients have not kept up with
those of their pediatric counterparts. Despite CR rates
of approximately 85% with adult regimens, the 3-year
Author affiliations EFS and overall survival (OS) rates remain below
and support
45%.8,9 Pediatric-inspired regimens that rely heavily
information (if
applicable) appear
on intensification of corticosteroids, pegylated aspar-
at the end of this aginase, vinca alkaloids, and antimetabolites are
article. currently being used for young adult patients, leading
Accepted on March to improvements in the EFS and OS rates when
2, 2020 and compared with historical controls.10-13 However, these
published at
agents are poorly tolerated by older patients, resulting
ascopubs.org on May
18, 2020: DOI https://
in poor survival rates. Therefore, newer and lower-
doi.org/10.1200/ intensity therapies incorporating novel immunother-
EDBK_280175 apies and now being tested for older patients with ALL.
mountable problem for many patients. The higher rate
of relapse among adults with ALL is probably attrib-
utable to higher-risk disease. For example, more adult
patients have adverse cytogenetics and molecu-
lar features (i.e., the Philadelphia chromosome or
Philadelphia-like signature) and persistent MRD. Sal-
vage chemotherapy regimens have shown only modest
activity for patients with relapsed or refractory ALL.14,15
Monoclonal antibodies, novel immunotherapies, and
kinase inhibitors for specific genetic subtypes are
entering the clinic in the upfront and relapsed/
refractory (R-R) setting, with promising results.
HOW DO I PROFILE ALL WITH CURRENT
MOLECULAR DATA?
Risk stratification by cytogenetics and molecular ge-
netics reflects the prognostic heterogeneity of ALL that
determines which patients are at a high risk of relapse
and should be considered for more intensive treat-
ment strategies, including allogeneic stem cell trans-
plantation (ASCT). Risk assessment at diagnosis based
on immunophenotypic and genetic factors will allow
stratification of patients into standard-risk and high-risk
categories. In addition, patient characteristics, in-
cluding advanced age, poor performance status, and
hyperleukocytosis, are all recognized adverse risk
factors predicting poor outcomes of chemotherapy. In
both pediatric and adult studies, persistence of MRD,
defined as more than 10 4 blasts, has proven to be

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Recent Advances in Managing Acute Lymphoblastic Leukemia
PRACTICAL APPLICATIONS
• Cytogenetics and molecular profiling are nec-
essary for appropriate risk stratification in pa-
tients with ALL.
• Assessment of the Philadelphia-like signature is
essential for decisions regarding postremission
therapy and treatment at relapse.
• The assessment of minimal residual disease
remains the most important assessment for risk
stratification in ALL.
• Novel immunotherapy agents are more effective
than conventional therapy for patients with re-
lapsed or refractory disease.
• The treatment of older patients with ALL re-
mains a difficult endeavor with high therapy-
related toxicity and poor long-term survival, and
therefore novel approaches are needed.
a major independent risk factor for relapse.16 Thus, MRD
assessment by either molecular- or flow-based approaches
has become standard clinical practice not only for pediatric
but also for adult patients.17
Immunophenotypic Classification
Determining the cell of origin (T-cell vs. B-cell ALL) and
specific immunophenotypes (e.g., Pro-B and Pre-B ALL)
were traditionally of prognostic importance in ALL18-20;
however, more recent reports dispute their prognostic
value.21 It remains essential to separate precursor B-cell
ALL from mature B-cell ALL (Burkitt) because these entities
are typically treated with different chemotherapy strategies.
Mature B-cell tumors typically express surface immu-
noglobulin and are negative for CD34 and terminal
deoxytransferase markers of immaturity. In B-cell ALL,
the expression of CD20 (. 20%) has consistently been
shown to be associated with disease resistance and poorer
outcomes,22,23 which can be ameliorated with the adminis-
tration of anti-CD20 immunotherapies, such as rituximab.24
T-cell ALL accounts for approximately 15% of ALL, and with
pediatric-based regimens adopting an MRD risk-stratified
approach, the outcomes of T-cell ALL may be superior to
those of B-cell ALL. Subgroup analysis from the large
Medical Research Council UKALLXII/Eastern Cooperative
Oncology Group (ECOG) 2993 trial demonstrated that, in
T-cell ALL, CD1a positivity with the absence of CD13 ex-
pression was associated with improved survival. 25 Early
T-cell precursor (ETP) ALL is a recently recognized
immunophenotypic high-risk subgroup of T-cell ALL. ETP
ALL has a characteristic immunophenotype characterized
by CD1aneg, CD8neg, and CD5weak with aberrant expression of
myeloid markers.26 Interestingly, ETP-ALL often harbors
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
somatic mutations typical of myeloid malignancies.27 In
a retrospective analysis, 17% of adult patients with T-ALL or
lymphoblastic lymphoma were found to have the charac-
teristic ETP-ALL immunophenotype. These patients, when
treated with hyper-CVAD (i.e., hyperfractionated cyclo-
phosphamide, vincristine, doxorubicin, and dexametha-
sone) had significantly lower remission rates (73% vs. 91%;
p = .03) and a shorter median OS (20 months vs. not
reached; p = .008).28 In contrast, in a cohort of pediatric and
adolescent patients treated with a pediatric regimen (Chil-
dren’s Oncology Group AALL0434), ETP-ALL was not as-
sociated with adverse outcomes, but postremission therapy
was based on MRD status.29
Cytogenetic Classification
The most common chromosomal abnormalities observed in
children with B-cell ALL are hyperdiploidy (. 50 chromo-
somes) and the ETV6-RUNX1 (t12;21) subtypes, both of
which are associated with favorable outcomes (Table 1).30
Adolescent and young adult patients with ALL have a much
lower incidence of hyperdiploidy and ETV6-RUNX131 and
a higher incidence of unfavorable cytogenetics, including
Philadelphia-positive ALL, hypodiploidy, and complex kar-
yotype. The most important cytogenetic abnormality is the
Philadelphia chromosome. It is seen in only 3% of pediatric
patients but approximately 25% of adults, and it increases
with age, representing approximately half of the cases in
patients older than age 60.32 Although the outcome of
patients with Philadelphia chromosome positive–ALL has
improved with the addition of a tyrosine kinase inhibitor
(TKI), it remains unclear whether young adults need an
intensive chemotherapy (IC) backbone and whether ASCT
is still necessary for patients who achieve molecular re-
mission. Single-agent imatinib or dasatinib plus cortico-
steroid therapy, pioneered by the Gruppo Italiano Malattie
Ematologiche dell’Adulto (GIMEMA),33,34 induced CR in
almost all patients without risk of induction death. With TKI
plus chemotherapy combinations, CR rate exceeded 95%,
but death occurred in 2% to 7% of the cases. In a ran-
domized trial from the Group for Research on Adult Acute
Lymphoblastic Leukemia,35 a combination of de-escalated
chemotherapy and TKI resulted in less induction toxicity
and noninferior CR and survival results compared with
standard chemotherapy plus TKI. In an MD Anderson
Cancer Center study, ponatinib combined with hyper-CVAD
led to an excellent 83% 2-year OS, even without ASCT.36
KMT2A (also known as the mixed lineage leukemia
gene [MLL] on 11q23)–rearranged ALL carries a poor
prognosis.30,37 The incidence of KMT2A ranges from 60% to
80% in infants with ALL. In children and adults, the in-
cidence of KMT2A gene rearrangements ranges from 4.5%
to 5.7%. One of the most common 11q23 abnormalities,
t(4;11), occurs in 2% of children and adults with ALL.
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 DeAngelo, Jabbour, and Advani

TABLE 1. Common Chromosomal and Molecular Abnormalities in B-Cell ALL

Cytogenetics Gene Incidence in Adults Incidence in Children
Hyperdiploidy (. 50 chromosomes) — 7% 25%–30%
t(12;21)(p13;q22) ETV6-RUNX1 (TEL-AML1) 2% 22%–25%
t(9;22)(q34;q11): Philadelphia chromosome BCR-ABL1 25% 2%–4%
t(4:11)(q21;q23) and other KNMT2A translocations KNMT2A 8%–10% 2%–3% (60%–80% in infants)
Low hypodiploid near triploid TP53 in low hypodiploid 8%–10% 2%–3%
t(1;19)(q23;p13) TCF3-PBX1 3% 4%
t(11;14)(q11), e.g., (p13;q11), (p15;q11) TCRα and TCRδ 20%–25% 10%–20%
BCR-ABL1-like, Philadelphia-like Various 10%–30% 15%
Ikaros IKZF1 25%–35% 12%–17%

KMT2A rearrangements seldom express CD10, and
therefore the blasts have a common immunophenotype of
CD19+, CD10 , CD15+, or CD65+. Interestingly, they are
associated with high levels of H3K79 methylation catalyzed
by the DOTL1 enzyme, suggesting a novel therapeutic
target.38,39 In addition, multiple studies have shown high
levels of FLT3 expression in patients with KMT2A rear-
rangements; therefore, inhibitors of FLT3 (a tyrosine kinase)
may also prove beneficial.40 In some patients, KMT2A gene
rearrangements are not detected by conventional cytoge-
netics, and commercially available dual-color KMT2A
probes can detect translocations in metaphase chromo-
somes by fluorescence in situ hybridization techniques.
TCF3-PBX1, associated with t(1;19) translocation, is char-
acterized by favorable outcomes with intensive treat-
ment. Hypodiploid ALL is a poor prognostic subtype, which
includes near-haploid (24–31 chromosomes), low-hypodiploid
(32–39 chromosomes), and high-hypodiploid (40–43 chro-
mosomes) groups. RAS and PI3K pathways are frequently
mutated in near-haploid ALL, whereas TP53 and IKZF are
often mutated in low-hypodiploid ALL.41 Therefore, germline
mutational screening of TP53 should always be performed in
these cases.
Molecular Classification
The Philadelphia-like subgroup, initially identified by means
of gene expression profiling, accounts for approximately
20% of young adult and adult B-cell ALL cases (Table 1).
These cases are characterized by a transcriptional profile
similar to that of Philadelphia-positive ALL but lack the t(9;22)/
BCR-ABL1 rearrangement.42-45 Instead, the underlying ge-
nomic lesions are heterogeneous, making its recognition
difficult and uneven between trials. Rearrangements in
CRLF2 are seen in approximately 50% of cases; rear-
rangements in the ABL class genes (ABL1, ABL2, CSF1R,
PDGFRA, PDGFRB), in roughly 10%; and JAK/STAT genes
(JAK1-3, IL7R, and CRLF2 mutations), less often (, 10%).
Deletions in IKZF1 occur in up to 80% of cases and are
associated with a particularly poor prognosis.46,47 In general,
patients with Philadelphia-like ALL have a poorer outcome
compared with other B-cell ALLs, and it remains unclear
whether they should receive ASCT up front or based on
MRD persistence.45 The Children’s Oncology Group is
testing ruxolitinib in patients with CRLF2-rearranged and
JAK-STAT dysregulated disease (NCT02723994).
The most common mutation in classic T-cell ALL is
NOTCH1, whereas DNMT3A and other myeloid-specific
mutations are more commonly seen in ETP-ALL.27 NOTCH1
can be targeted by the gamma-secretase inhibitors, which
have been tested in patients with advanced late-stage
disease, with some durable responses but at the expense of
gut toxicity.48
Minimal Residual Disease
Patients with detectable residual blasts after chemotherapy
(MRD positive, typically defined as more than 10 4 blasts)
are seldom cured with chemotherapy alone. In pro-
spective trials,17,49,50 the OS was between 60% and 80%
with chemotherapy alone in patients with MRD-negative
status, even in high-risk subsets and Ph-positive ALL.
Conversely, patients with MRD-positive status benefit par-
tially from ASCT but with OS rates of 50% or less in intention-
to-treat analyses because of the cumulative effects of
pretransplantation and post-transplantation relapse and
transplant-related deaths.4,51,52
Monitoring MRD with real-time quantitative polymerase
chain reaction, flow cytometry, or high-throughput–based
platforms should be considered a standard practice for the
treatment of patients with ALL because it is the best pre-
dictor of OS. Similar robust prognostic data are seen in both
B-cell and T-cell ALL. In the analysis of standard-risk pa-
tients enrolled on the German Multicenter Study Group for
Acute Lymphoblastic Leukemia study, early MRD clearance
before day 24 was associated with a favorable outcome
(relapse rate of 0% at 3 years), whereas MRD positivity
lasting beyond week 16 predicted a relapse rate of 94%.53
Therefore, patients who achieve CR but fail to achieve
a negative MRD status remain at high risk of early relapse

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Recent Advances in Managing Acute Lymphoblastic Leukemia
and should seek alternative therapy.4 Similarly, MRD status
before SCT is also a powerful indicator for post-transplantation
outcomes and disease resistance.54
MRD is such a powerful predictor for relapse, so it is cur-
rently used to guide postinduction decisions. Bassan et al55
allocated patients to maintenance or SCT based on MRD
status at the end of intensive therapy (approximately
5 months from attaining CR) regardless of their cytogenetic
and clinical risk score at diagnosis, resulting in an im-
pressive 75% 5-year OS rate for nontransplanted patients
attaining MRD-negative status. This approach is being used
by other large cooperative groups with similar success.56
Taken together, these data suggest that MRD may indeed
be the most important predictor of OS for patients with ALL.
Future Directions
We are entering an intensive phase of clinical investigations
using next-generation sequencing data for the exploration of
individualized or subset-specific treatment algorithms.
Therefore, it will be crucial to design prospective clinical
studies with modular data to evaluate optimal strategies
for specific patient subtypes, or “personalized” medicine,
testing immunotherapy and combinations of molecularly
targeted drugs or drug combinations.
TREATING RELAPSED-REFRACTORY ALL: TOO MANY
OPTIONS, WHICH ONE TO PICK?
Therapies targeted toward specific transcripts (e.g., BCR-
ABL1 tyrosine kinase oncoprotein by TKIs) and specific
leukemic cell surface antigens (e.g., CD20, CD22, and
CD19 monoclonal antibodies) are major breakthroughs in
the management of ALL.57 Historically, relapsed or re-
fractory (R-R) ALL was associated with a dismal prognosis,
with a cure rate of less than 10%.14,58 The CR rates with
standard chemotherapy regimens are 30% to 40% in first
relapse and 20% to 25% in second relapse. Accordingly,
only 10% to 30% adult patients with relapsed ALL proceed
to ASCT, which is the only curative option in this setting.14
Recent developments of monoclonal antibodies, bispecific
antibody constructs, and CAR T-cell therapies have revo-
lutionized the treatment of ALL, resulting in U.S. Food and
Drug Administration (FDA) approvals of blinatumomab in
2014 and inotuzumab and tisagenlecleucel in 2017 as ALL
salvage strategies.59-61 Their use in combination with other
treatment modalities in the salvage and frontline settings are
under investigation.
Anti-CD19 Bispecific T-Cell Engager:
Blinatumomab
Blinatumomab is an anti-CD19–directed CD3 bispecific T-cell
engager constructed with BiTE antibody technology.62-64 It
consists of a recombinant monoclonal antibody com-
posed of an anti-CD19 fragment antigen-binding region
joined by a short link to an anti-CD3 fragment antigen-
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
binding region.62,63 In the confirmatory phase II study of 189
patients with R-R Philadelphia-negative ALL, blinatumomab
was associated with a CR-plus–CR with partial hematologic
recovery rate of 43%. The median response duration was 9
months, and the median OS was 6 months.64
After these results, a phase III trial (TOWER study) was
conducted: more than 400 patients with R-R Philadelphia-
negative ALL were randomly assigned (2:1) to blinatumo-
mab (n = 271) or standard of care (n = 134; Table 2).59 The
response rates were 44% and 25%, respectively (p , .001).
Molecular remission rates among responders, defined as
fewer than 10 4 blasts in the first 12 weeks, were 76% and
48%, respectively. Blinatumomab prolonged survival, the
primary study endpoint; the median OS was 7.7 months
(95% CI, 5.6–9.6) versus 4.0 months (95% CI, 2.9–5.3; p =
.01; hazard ratio, 0.71). A total of 24% of the patients in
each group underwent ASCT.65
A recent phase III study demonstrated the superiority of
blinatumomab for 208 children and adolescent young
adults in salvage 1 and randomly assigned (1:1) to bli-
natumomab or standard of care.66 Blinatumomab induced
a higher rate of measurable residual disease negativity (79%
vs. 21%; p , .001) and a higher 2-year OS (79% vs. 59%;
p = .005).
Blinatumomab was evaluated in the phase II ALCANTARA
trial with 45 patients who had R-R Philadelphia-positive
ALL.67 Thirty-six percent achieved a response. The median
relapse-free survival and OS were 6.7 months and 7.1
months, respectively; 44% of patients underwent ASCT.
Furthermore, blinatumomab was given with TKIs to 20 pa-
tients with R-R Philadelphia-positive ALL or chronic myeloid
leukemia in the lymphoid blast phase. The response rate was
65%. The median survival was 14 months.68
Gökbuget et al69 assessed blinatumomab in 113 patients
with ALL in MRD-positive CR. Approximately 78% of patients
achieved MRD negativity after one cycle and 80 after two
cycles. With a median follow-up of 29 months, the median OS
was 36.5 months and the relapse-free survival was 18.9
months. The median OS with achievement of MRD negativity
was 38.9 months compared with 12.5 months for patients with
persistent MRD. These findings were confirmed when com-
pared with historical data via propensity score matching.70
Blinatumomab is being evaluated in the frontline setting
in combination with chemoimmunotherapy in Philadelphia-
negative ALL and with TKIs in Philadelphia-positive ALL.
Anti-CD22 Antibody-Drug Conjugate:
Inotuzumab Ozogamicin
Inotuzumab ozogamicin is a novel anti-CD22 monoclonal
antibody conjugated to the toxin calicheamicin.71 In a single-
institution, phase II study of patients with R-R ALL, inotu-
zumab was administered at a starting intavenous dosage of
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 DeAngelo, Jabbour, and Advani
TABLE 2. Relapsed and Refractory Trials in ALL
Clinical Trial Treatment Setting
Blinatumomab
TOWER4 R-R Ph ALL
12
ALCANTARA R-R Ph+ ALL
Inotuzumab Ozogamicin
INO-VATE5 R-R Ph– and Ph+
ALL
Inotuzumab plus mini-hyper-CVD 6 R-R Ph– ALL
blinatumomab23
CAR T
ELIANA82 R-R ALL
Abbreviations: ALL, acute lymphoblastic leukemia; mini-hyper-CVD, mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone; NR, not
reached; Ph, Philadelphia chromosome; ORR, overall response rate; R-R, relapsed or refractory; S1, salvage 1; S2, salvage 2; S3, salvage 3.
a
Measured by flow cytometry.
b
Within two cycles.
1.3 to 1.8 mg/m2 every 3 to 4 weeks. Forty-nine patients were
treated.72 The objective response rate was 57%, and the
median survival was 5.1 months. Nearly half of the patients
treated with inotuzumab proceeded to ASCT. To minimize
toxicities and based on pharmacokinetic and pharmaco-
dynamic data, inotuzumab was administered intravenously
on a weekly basis at 0.8 mg/m2 on day 1, followed by 0.5 mg/
m2 on days 8 and 15, every 3 to 4 weeks in 40 patients. The
study yielded a similar response rate to inotuzumab given
every 3 to 4 weeks (59% vs. 57%), with a median survival of
9.5 months.73 Weekly administration of inotuzumab resulted
in fewer adverse events, including lower rates of veno-
occlusive disease (VOD). In a separate multicenter phase
II trial in heavily pretreated patients with R-R ALL, inotu-
zumab therapy resulted in a remission rate of 66%, with 78%
of patients who achieved CR becoming MRD negative. The
median survival was 7.4 months.74
These results led to a randomized trial comparing inotu-
zumab with physician’s choice of chemotherapy in R-R
ALL.60,74 The response rate was 88% (CR, 81%) with ino-
tuzumab and 32% (CR, 29%) with standard of care (p ,
.0001). Among responders, the MRD negativity rates were
78% and 28% (p , .0001), respectively. The median
survival was 7.7 versus 6.7 months (p = .02; hazard ratio,
0.77); The 2-year survival rate was 23% versus 10%.75
Serious toxicities included VOD after ASCT, mainly in pa-
tients who received double alkylators in pretransplantation
conditioning. Age was also a risk factor for VOD.
Inotuzumab was assessed in 48 children, adolescents, and
young adults (median age, 9; range, 1–21 years).76 The
objective response and MRD negativity rates were 62% and
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
Median Overall Survival Minimal Residual Disease
Patients Response (months) Negativitya
271 ORR: 44% 7.7 76%
45 ORR: 36% 7.1 88%b
164 ORR: 74% 7.7 78%
89 ORR: 79% S1: 25 82%
S2: 6
S3: 7
79 ORR: 81% NR 100%
65%, respectively. The 12-month survival rate was 40%.
The VOD rate was 10.4%; it was 26% after ASCT.
Inotuzumab was also evaluated with a dose-reduced mini-
hyper-CVD regimen (i.e., mini-hyperfractionated cyclo-
phosphamide, vincristine, and dexamethasone) with or
without blinatumomab in 89 patients with R-R ALL.77 The
response rate was 79%, with 82% of responders achieving
MRD negativity. The 2-year progression-free survival and OS
rates were 52% and 39%, respectively. Among patients
treated in salvage 1, the 2-year survival rate was 51%. The
VOD rate was 6%.
Better outcomes were obtained in patients who received
inotuzumab- or blinatumomab-based therapies in first
salvage.65,78-81 This was particularly notable in patients who
achieved a negative MRD status and received subsequent
ASCT. ASCT performed in subsequent salvages did not
confer a survival advantage.80
CAR T-Cell Therapies
CAR T Cells are genetically modified autologous T lym-
phocytes engineered to express binding sites of specific
antibodies, such as a receptor against CD19. These T cells,
harnessed from the patients’ own immune systems, target
the malignant cells.
In a phase II multicenter study, 79 children and young
adults with relapsed or refractory CD19+ B-ALL received
a single infusion of tisagenlecleucel, CD19 CAR T-cells.61,82
Among evaluable patients, the overall response rate was
81%, with all patients whose disease responded achieving
negative MRD. The 24-month relapse-free survival and OS
rates were 62% and 66%, respectively. The CAR T cells
 Recent Advances in Managing Acute Lymphoblastic Leukemia
persisted for a median of 168 days (range, 20–617 days),
suggesting that immunosurveillance with these products
may be long lasting. Grade 3 and 4 cytokine release syn-
drome (CRS) and neurotoxicities were encountered in 49%
and 40%, respectively, with 48% needing an intensive care
unit stay. This led to the approval of tisagenlecleucel for R-R
ALL for patients up to age 25 after failure of two previous
therapies.
For 53 adults with heavily pretreated B-ALL who received
the CAR T-cell infusion, the CR rate was 83%, including 32
(67%) of 48 evaluable patients achieving negative MRD.83
Better outcomes were observed for patients with low disease
burden ( 5% bone marrow blasts) at the time of CAR T-cell
infusion, with a median EFS of 10.6 months compared with
5.3 months and a median OS of 20.1 months compared
with 12.4 months for patients with a high disease burden.
Several strategies to optimize CAR T-cell activities and
minimize their toxicities have been explored. The use of
CD19 CAR T cells with a lower-affinity CD19 binder with
a fast off-rate would lead to physiologic T-cell activation,
reduced toxicity, improved engraftment, and potential long-
term persistence to deliver sustained responses.84 In a pilot
trial of 16 adults treated, the objective response and MRD
negativity rates were 87% each. The 6-month OS rate was
66%. No grade 3 cases of CRS were reported; three patients
experienced reversible grade 3 neurotoxicity.85
To circumvent CD19 escape as a cause of relapse after
CD19 CAR T-cell therapy, CD22-targeted CAR T-cell ther-
apy has been developed.86 Of the 15 children and adults
with R-R B-ALL, most of whom were previously treated with
CD-19–directed immunotherapy, 11 (73%) achieved CR
after treatment with at least 1  106/kg body weight of CAR
T cells. Encouraging results from a phase I trial of dual
CD19/CD22 bispecific CAR T-cells in 21 children and adults
with R-R ALL reported grade 3 to 4 CRS and neurotoxicity in
only two patients (10%), with CR and MRD negativity rates
of 86% and 81%, respectively.87
Current therapies use autologous lymphocytes, which can
be scarce and difficult to expand. New platforms provide an
off-the-shelf approach, with cells derived from healthy
volunteer donors. In the phase I dose escalation trial in
children and adults with R-R ALL, the objective response
and MRD negativity rates were 82% and 71%, re-
spectively.88 Treatment was tolerated, with only moderate
CRS. Off-the-shelf products targeting CD22 and allogeneic
cord blood–derived natural killer cells are being developed.
BH3 Mimetics
Preclinical studies have demonstrated activity of the BH3
mimetics venetoclax and navitoclax in B-cell and T-cell ALL
cell lines.89-91 Venetoclax has demonstrated particularly
strong activity in MLL-rearranged B-cell ALL, and both
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agents have demonstrated single-agent and synergistic cell
killing when combined with chemotherapy because of the
upregulation of Bcl-2 in these cell lines.89,90 In a phase I trial,
36 patients with R-R ALL (median age, 27; range, 6–72
years) were treated with venetoclax and navitoclax in
combination with chemotherapy. The objective response
rate was 50%; the 6-month CR duration rate was 43%.92
Preliminary results of the combination of venetoclax with
low-intensity chemotherapy in newly diagnosed older pa-
tients unfit for IC are promising, with objective response and
MRD negativity rates of 91% and 100%, respectively.93
Future Directions
Given the encouraging results achieved with monoclonal
antibodies, bispecific antibody constructs, and CAR T cells,
the therapeutic tools necessary to improve outcomes of
patients with adult ALL may now be available. These
treatment modalities are not competitive but rather com-
plementary, and they could be administered sequentially to
produce the deepest remissions possible. Their rational
combination in the frontline setting is ongoing and may
reduce the need for long-term IC and obviate ASCT for many
patients.
THE OLDER PATIENT WITH ALL
The definition of “older” or “elderly” adults with ALL has
typically included patients age 60 and older. Historically,
their prognosis has been dismal, with a 5-year OS of ap-
proximately 20%.94,95 This prognosis has been attributed to
adverse biology and the inability of older patients to tolerate
IC. However, the advent of new immunotherapies and TKIs,
incorporation of MRD to guide therapy, and the increasing
safety of ASCT for older patients are leading to improved
outcomes. However, these new approaches make man-
agement of these cases more complicated. In this section,
we focus on disease biology, standard treatment, and new
approaches to therapy in the older patient with ALL.
Biologic Concerns for Older Patients With ALL
The incidence of high-risk genetic abnormalities among
older adults with ALL is high. The Philadelphia chromosome
is present in approximately 50% of these patients.94,96
Before the advent of TKIs, the Philadelphia chromo-
some was associated with a poor prognosis; however, TKIs
have dramatically improved outcomes.97 More recently,
the Philadelphia-like signature has been identified in
approximately 24% of older adults and has been asso-
ciated with a poor outcome.43 The incidence of specific
fusions varies with age, with older adults expressing high
levels of CRLF2.43 Low hypodiploidy or near triploidy,
complex cytogenetics, IKZF1 mutations, chromosome 17
abnormalities, and KMT2A rearrangements are more
common, and high hyperdiploidy is less common, in older
adults with ALL.98-103 Finally, older patients have a higher
2020 ASCO EDUCATIONAL BOOK | asco.org/edbook 335
 DeAngelo, Jabbour, and Advani
incidence of the B-cell (89%) compared with T-cell (66%)
phenotype.98,104
Outcomes of Standard Treatment for Patients With
Philadelphia Chromosome–Negative ALL
Standard ALL treatment includes intensive induction and
postremission therapy. This can be challenging for older
adults because of their comorbidities: diabetes, cardiac
dysfunction, pulmonary abnormalities, neuropathy, poly-
pharmacy, and decline in performance status.94,98 Although
poor outcomes have been reported in clinical trials, out-
comes are almost certainly worse when evaluating “all
comers” because many patients do not receive treatment.
In a Surveillance, Epidemiology, and End Results data-
base of patients age 60 or older with ALL, the median OS
was 4 months, and the 3-year OS was 12.8%.98,105 In the
largest study conducted with IC for older adults with
Philadelphia-negative ALL, the German Multicenter
Study Group for Acute Lymphoblastic Leukemia trial,98,106
268 patients older than age 55 were treated with a modified
intensive Berlin-Frankfurt-Munster (i.e., BFM) regimen
followed by postremission therapy and maintenance. Rit-
uximab was administered to patients with CD20-positive
disease. The 5-year OS was only 23% despite a relatively
young median age (67 years) and 62% of patients having an
ECOG performance status of 0 to 1. An amendment was
incorporated into the trial, adding triple intrathecal che-
motherapy, adding asparaginase during postremission
therapy, and increasing the dosages of methotrexate and
cytarabine. The 2-year OS increased from 33% to 52%;
however, long-term outcomes remained disappointing.98,106
With most IC, the rates of CR have decreased with ad-
vancing age and the rates of early death have increased
(Table 3).106 Increased age has been associated with
a higher risk of infections during induction (81% vs. 70%)
and more dose reductions (46% vs. 28%).107 In patients age
60 or older treated with hyper-CVAD, the death rate in CR
has been approximately 34%.94,108 Because of the in-
creased rates of early deaths, most IC regimens have used
a standard backbone with dosage reductions to avoid tox-
icities. The Cancer and Leukemia Group B reduced the
number of days of steroids to 7 days (from 21 days) during
induction for older patients.109 In a PETHEMA trial, re-
searchers increased the 2-year OS from 39% to 52% by
TABLE 3. Rates of Complete Remission and Early Death by Age Group
in the German Multicenter Study Group for Acute Lymphoblastic
Leukemia Study14
Age Range (years) Complete Remission Rate Early Death Rate
55–65 84% 7%
66–75 74% 14%
. 75 52% 37%
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
removing asparaginase and cyclophosphamide.94,110 Al-
though targeting CD20 with rituximab in combination with
chemotherapy has demonstrated benefit in patients younger
than age 60 with B-ALL, incorporating this agent for patients
who are at least age 60 has not demonstrated a benefit.94,111
This finding may be related to more deaths in CR. Ribera
et al112 evaluated a pediatric-inspired IC in a younger group of
older adults (age 55–65) to see whether results were more
favorable in this subgroup. Despite an improvement in out-
come, the 2-year EFS was only 37%,112 emphasizing the
need for novel strategies.
Patients With Philadelphia Chromosome–Positive ALL
TKI treatment has improved the outcomes for Philadelphia
chromosome–positive ALL substantially. First-generation
TKIs, such as imatinib, have demonstrated higher rates
of remission than chemotherapy alone and low rates of
toxicity.98,113 However, remission durations have typically
been short (median duration, 8 months with imatinib).34
Later-generation TKIs, such as dasatinib, have demon-
strated improved results.33 However, despite all patients
achieving a hematologic remission, only 20% achieved
a major molecular remission, and the 20-month OS and
disease-free survival rates were 69.2% and 51.1%, re-
spectively.33 Twelve of the 17 patients who experienced
relapse had the resistant T315I Bcr-Abl mutation,33 the
dominant mechanism of relapse among patients treated
with earlier-generation TKIs.33,98,114 Ponatinib is the only
active TKI in this setting. The GIMEMA group evaluated
ponatinib in combination with steroids.98,115 The rates of CR,
complete molecular remission, and 1-year OS were 95%,
46%, and 87.5%, respectively. Thirteen serious adverse
events related to ponatinib occurred (in 44 patients).94,115
Therefore, caution is necessary, given the cardiovascular
risk profile of ponatinib, and the drug dose should be re-
duced once complete molecular remission is achieved.
These results are encouraging, however, the median follow-
up is short (11.4 months). Longer follow-up is needed.
For fit older adults, TKI therapy can be combined with IC.
Imatinib has been combined effectively with various che-
motherapy regimens: UKALLXII/ECOG 2993, the North
Italian Leukemia Group multiagent chemotherapy back-
bone, GRAAPH-2005 with reduced-intensity induction, and
hyper-CVAD.35,116-119 Although the CR rates have been more
than 90%, higher than those of chemotherapy alone, the
rates of EFS and OS have varied (EFS, 33%–42%; OS,
38%–48%).35,116-119 This variation may be related to the
regimen, median patient age, and percentage of patients
ultimately undergoing ASCT. Notably, the median age of
patients in most of these trials was in the mid-40s, and OS
was significantly shorter in patients age 60 or older,
compared with those younger than age 60, stressing the
need for more effective approaches for older adults.116
 Recent Advances in Managing Acute Lymphoblastic Leukemia
The second-generation TKIs dasatinib and nilotinib
have been combined with chemotherapy, with EFS and
OS rates in the range of 42% to 55% and 46% to 72%,
respectively.114,116,120-122 Finally, a phase II trial evaluated
the third-generation TKI ponatinib with hyper-CVAD.36,98
This trial enrolled 66 patients, with 20 patients younger
than age 60. The rates of CR and complete molecular re-
mission were 100% and 77%, respectively, with a 3-year OS
of 77%. These results are impressive and demonstrated
increased EFS and OS compared with hyper-CVAD and
other TKI-based therapies in a propensity analysis.98,123 This
analysis, in addition to the single-agent data, suggests
improved outcomes with successive-generation TKIs, al-
though no randomized trials have been reported. In addi-
tion, among patients with deep molecular remissions, there
were long-term survivors without ASCT. However, the dose
intensity of ponatinib correlated with adverse events, and
the trial was amended for risk-adapted dosing, because
three of 39 patients had a myocardial infarction at the
continuous dose of 45 mg.36 Given the potential cardio-
vascular risks of ponatinib and the intensive nature of hyper-
CVAD, this regimen is suitable only for truly fit older patients;
strict organ function criteria were included in this trial.
Given the short duration of remissions with TKIs alone and
toxicities when combining with IC, other approaches are
being evaluated, including combining dasatinib with im-
munotherapy, such as blinatumomab (SWOG 1318,
NCT02143414), or combining various TKIs with low-
dose chemotherapy.
Ongoing and Recent Clinical Trials for Patients With
Philadelphia-Negative ALL
In consideration of the toxicities with standard IC, many
current trials are reducing chemotherapy and adding novel
agents. Inotuzumab, an anti-CD22 antibody conjugated to
the cytotoxic agent calicheamicin, demonstrated higher
rates of CR, MRD, and OS compared with standard che-
motherapy in patients with R-R B-ALL due for salvage
chemotherapy.60 This led to FDA approval of inotuzumab for
the treatment of R-R B-ALL. The drug is generally well
tolerated, with a unique toxicity of hepatic VOD. Sub-
sequently, inotuzumab was combined with low-intensity
chemotherapy (mini-hyper-CVD) for patients with Philadelphia-
negative B-ALL who were at least age 60.124 Fifty-two
patients were treated (median age, 68). The incidence of
VOD was 8%, with a 12% incidence of treatment-related
deaths.124 At a median follow-up of 29 months, the 2-year
progression-free survival was encouraging at 59%.124 In
a propensity analysis comparing mini-hyper-CVD/inotuzumab
with or without blinatumomab with hyper-CVAD, the anti-
body plus low-intensity treatment demonstrated a higher
response rate, lower rates of early death, lower rates of death
in remission, and higher 3-year EFS (64% vs. 34%) and OS
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
(63% vs. 34%) compared with hyper-CVAD.125 A phase III
trial of mini-hyper-CVD with or without inotuzumab is planned.
Blinatumomab, an anti-CD19 bispecific T-cell engaging
antibody, has been FDA approved for R-R B-ALL and has
also demonstrated superiority to standard chemotherapy.59
This drug’s unique toxicity profile has included CRS and
neurotoxicity reminiscent of that seen with CAR T cells but at
a much lower incidence. In a phase II trial (SWOG1318),
patients at least age 65 with newly diagnosed Philadelphia-
negative B-ALL were treated with blinatumomab for in-
duction, then received postremission therapy, followed by
maintenance therapy with prednisone, vincristine, metho-
trexate, and mercaptopurine. Twenty-nine eligible patients
were treated (median age, 75).126 The median bone marrow
blast count was 86.5%, and 34% of patients had poor-risk
cytogenetics. The rate of response (CR and CR with in-
complete count recovery) was 66%, with no early deaths. At
a median follow-up of 1.3 years, the estimated 1-year
disease-free survival and OS were 58% and 67%, re-
spectively.126 Further follow-up will be needed to determine
the durability of these responses. A second clinical trial,
A041703, is sequencing inotuzumab and blinatumomab
treatment.
For fit older adults, a recent U.S. Intergroup trial (ECOG
1910) completed accrual (ages 30–70). Patients received
an intensive induction and postremission therapy, which
was modified based on age. There was a random assign-
ment for patients who were MRD negative to either continue
standard therapy or receive blinatumomab followed by
further chemotherapy. The results of this trial are eagerly
awaited.
Finally, the Bcl-2 inhibitor venetoclax is being evaluated in
both B-ALL and T-ALL. Bcl-2 is overexpressed in ALL.127 An
ongoing trial evaluated the Bcl-2 inhibitor navitoclax plus
venetoclax in combination with chemotherapy in R-R ALL.
Despite a heavily pretreated population, the response rate
was encouraging at 56%.128 Another trial is evaluating
venetoclax in combination with low-intensity chemotherapy
for older patients with newly diagnosed ALL.129
Future Directions for Older Patients With ALL
Multiple novel agents are being evaluated in Philadelphia-
positive and -negative ALL. Incorporation of these agents
with less-intensive chemotherapy is likely to improve out-
comes of older adults, and clinical trials are evaluating these
approaches. The presence of Philadelphia-like alterations
and MLL rearrangements may make TKI-based therapy and
MLL inhibitors in combination with low-dose therapy an-
other option for these patients. Although CAR T cells are not
yet FDA approved for adults older than age 26, these agents
are being used in clinical trials; as their toxicities are opti-
mized, they are likely to become an option for older adults,
2020 ASCO EDUCATIONAL BOOK | asco.org/edbook 337
 DeAngelo, Jabbour, and Advani

given their impressive clinical activity.83 The use of MRD to
guide therapy will probably be incorporated into future trials,
particularly because blinatumomab is now FDA approved in
the MRD-positive setting. Finally, as outcomes with
reduced-intensity ASCT are improving and there is an
increasing availability of donors, transplantation is becoming
another option for patients who previously would not have
been candidates. Recent studies demonstrate encouraging
results for appropriate “elderly” candidates.130

AFFILIATIONS CORRESPONDING AUTHOR

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Daniel J. DeAngelo, MD, PhD, Dana-Farber Cancer Institute, 450
MA Brookline Ave., Boston, MA 02215; email: daniel_deangelo@dfci.
2
The University of Texas MD Anderson Cancer Center, Houston, TX harvard.edu.
3
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if
applicable) are available with this article at DOI https://doi.org/10.1200/
EDBK_280175.

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