clinical review

Acute Lymphoblastic Leukemia in the Older Adult

Ibrahim Aldoss, MD1; Stephen J. Forman, MD1; and Vinod Pullarkat, MD1
abstract

Acute lymphoblastic leukemia (ALL) in older adults presents a real challenge as a result of adverse disease
biology and comorbidities that preclude delivering curative regimens. Conventional chemotherapy approaches
have generally yielded unsatisfactory results in older patients with ALL as a result of excessive induction
mortality, chemotherapy resistance of the leukemia, and the need to omit or dose reduce key drugs during the
course of therapy because of adverse effects. Philadelphia chromosome–positive ALL represents about a
quarter of newly diagnosed older adults, and the striking single-agent activity and excellent safety profile of
tyrosine kinase inhibitors has allowed incorporation of these agents into therapy, significantly improving the
outcome of older adults with Philadelphia chromosome–positive ALL. Allogeneic hematopoietic cell trans-
plantation using reduced-intensity conditioning is a potentially curative approach in the older adult with ALL, and
ironically, it may be better tolerated than intensive combination chemotherapy in a subset of older patients with
ALL. Immunotherapies such as chimeric antigen receptor–modified T-cells, the bispecific T-cell–engaging
antibody targeting CD19 (blinatumomab), and the antibody-drug conjugate targeting CD22 (inotuzumab) have
shown safety and exceptional activity even in advanced ALL, and the efficacy of these agents has been observed
irrespective of patient age. Several promising studies tailored specifically toward older adults with ALL are
ongoing, with the majority of them incorporating novel immunotherapies, targeted therapies, or third-generation
tyrosine kinase inhibitors into the front-line treatment regimen.
J Oncol Pract 15:67-75. © 2019 by American Society of Clinical Oncology

INTRODUCTION also discuss ongoing studies of novel agents that could

Although uncommon among older patients (age $ 60
years), acute lymphoblastic leukemia (ALL) presents a
real challenge in older patients for a variety of reasons.
ALL in such patients often carries high-risk genetic
alterations that confer resistance to conventional
chemotherapy. Often, older patients have comorbid-
ities that make it difficult to treat them with the same
intensity as younger patients. In addition, certain
ASSOCIATED drugs, such as asparaginase (ASP) and vincristine, are
CONTENT
more toxic in older patients, resulting in avoidance or
See accompanying
dose reduction of these key agents in older adults. The
commentary on
page 77 prolonged nature of ALL treatment regimens and the
Author affiliations requirements for frequent hospital visits are challenges
and support for many older adults. Moreover, there is often a
information (if misperception that all ALLs in older adults are incur-
applicable) appear able and that these patients are unable to tolerate even
at the end of this
modified regimens. This belief precludes a subset of fit
article.
elderly patients from receiving therapies with curative
Accepted on August
27, 2018 and intent, including allogeneic hematopoietic cell trans-
published at jop. plantation (HCT).
ascopubs.org on
February 12, 2019:
In this review, we discuss the biology and treatment of
DOI https://doi.org/10. ALL in older adults and, given the available data,
1200/JOP.18.00271 present our approach for treating these patients. We
lead to better treatment outcomes for older adults with
ALL. For the purpose of discussion, we refer to
patients $ 60 years old as older adults based on an
arbitrary age when intensive treatments such as
pediatric-inspired chemotherapy regimens become
challenging to deliver.
EPIDEMIOLOGY AND OUTCOMES OF THE OLDER ADULT
WITH ALL
ALL constitutes only 0.4% of all newly diagnosed
cancers in the United States, with an estimated 5,970
patients diagnosed in 2017. The median age at ALL
diagnosis is 15 years, and only 20% of patients are
diagnosed after the age of 55 years. In contrast, 51%
of ALL-related deaths occur in patients $ 55 years
old.1 This striking discrepancy between ALL incidence
and leukemia-related mortality in the older adult
highlights the detrimental impact of increasing age on
ALL outcomes.
Treatment outcomes of ALL in older adults have been
dismal, with a 5-year overall survival (OS) rate of ap-
proximately 20%.2-7 Furthermore, in older patients
with ALL, there is an inverse correlation between

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 Aldoss, Forman, and Pullarkat
increasing age and survival.6,8,9 Registry data suggest
modest improvement over time in ALL outcomes among
older adults in the United States (3-year OS: 1980 to 1989 v
1990 to 1999 v 2000 to 2011, 10% v 11% v 16%, re-
spectively; P , .001).9 A similar incremental improvement
in survival over time for older patients with ALL was wit-
nessed in the Dutch registry as well, but this progress was
predominantly observed among patients in their seventh
decade of life. Outcomes for patients older than age 70
years remained essentially unsatisfactory.10
GENETICS OF ALL IN OLDER ADULTS
ALL in older adults has a distinct genomic landscape that
could partially explain their poor outcomes. ALL in these
patients is enriched with high-risk cytogenetic and genetic
abnormalities, whereas favorable alterations are rare.
Philadelphia chromosome (Ph) is frequently encountered
in older adults with ALL and has been reported in ap-
proximately one third of patients.2,3,5,8,11 Other unfavorable
cytogenetics that are observed at a higher frequency in
older adults with ALL include t(8;14), complex karyotype,
low hypodiploidy, and t(14;18).12,13 Moreover, older adults
with ALL more frequently carry adverse genetic alterations
such as TP53 and IKZF1 mutations.13,14
Ph-like ALL is another high-risk entity that has been re-
ported in as many as 24% of older patients with ALL in the
United States,5 but its incidence was found to be lower in
this age group in a German cohort (, 10%).15 This dis-
crepancy is likely a result of the higher Latino population in
the United States, in whom this entity is more common.16
TREATMENT OF THE OLDER ADULT WITH ALL
Chemotherapy Approaches for Ph-Negative ALL
Conventional chemotherapy approaches have, in general,
yielded unsatisfactory results in older patients with Ph-
negative ALL as a result of excessive treatment-related
mortality, particularly during induction2-4,6,17,18; chemo-
therapy resistance; and the need to omit or dose reduce key
drugs during the course of therapy because of adverse
effects.
The contribution of the high induction mortality rate to the
poor outcome of older adults with ALL remains under-
recognized. Studies have repeatedly emphasized the ex-
cessive induction mortality in older patients with ALL when
intensified standard regimens have been used, and this has
prompted several protocols to amend their original in-
duction regimen. For instance, induction of older adults
($ 55 years old) with a five-drug regimen in the Programa
Español de Tratamientos en Hematologı́a (PETHEMA) ALL-
96 study resulted in an induction mortality rate as high as
70%, which translated into a low complete remission (CR)
rate (30%). This protocol was subsequently amended, and
both ASP and cyclophosphamide were eliminated from
induction; this change led to an improved induction
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mortality rate (22%).17 Likewise, in the UKALL14 (United
Kingdom Acute Lymphoblastic Leukaemia) trial, a marked
decline in induction mortality was observed in patients
$ 55 years old with reduction in pegylated (PEG) ASP and
anthracycline dose.18
The high treatment-related mortality in older adults with
ALL is also encountered after induction, and it can be
substantial, especially if highly myelosuppressive regimens
are used. Although induction of older patients (. 60 years
old) with hyperfractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone (hyperCVAD) yielded an
encouraging CR rate (84%) with an induction mortality rate
of only 10%, 34% of patients subsequently died in re-
mission and the majority of deaths were a result of in-
fectious complications.2
Application of modified pediatric-inspired ALL regimens in
older adults has been attempted. One key issue has been
determining the dose of ASP that can be administered
without excessive toxicity. The German Multicenter Study
Group for Adult ALL successfully introduced reduced-dose
PEG-ASP (500 IU/m2) in postinduction phases and have
reported on its safety and encouraging results in patients
# 75 years old.6 A modified protocol based on the Dana-
Farber Cancer Institute ALL regimen was applied in older
patients with ALL (. 50 years old). The study met the
primary end point, with a 1-year OS of 63%. However, the
administration of the standard PEG-ASP dose (2,000 IU/m2)
resulted in a high rate of hyperbilirubinemia, and this led
to amending the PEG-ASP dose twice during the study
course to a dose of only 500 IU/m2.19 The Spanish
PETHEMA group compared outcomes of older adults (55 to
65 years old) with ALL treated either on intensive pediatric-
inspired protocols (ALL-HR03 and ALL-HR11) or on a less
intensive adult protocol (ALL-OLD07). Their analysis
showed superiority of intensive regimens with regard to CR
rate, OS, and event-free survival, with comparable in-
duction mortality rates.20
We conclude that application of standard chemotherapy
regimens (both pediatric inspired and adult type) in older
patients with ALL results in excessive toxicity and induction
mortality and is generally associated with dismal long-term
outcomes. Although there are data showing tolerability of
lower doses of ASP in older adults, this agent should not be
used in the older adult outside of a clinical trial. There may
be opportunities to tailor these regimens specifically for
older adults by adjusting doses of conventional agents or
adding novel agents, but this is best done as part of a
clinical trial, which would be the preferred option for all
older adults with ALL.
Treatment of Older Patients With Ph-Positive ALL
Ph-positive ALL represents the largest subset of ALL in older
adults. Although Ph-positive ALL has been viewed histor-
ically as a high-risk disease, the introduction of tyrosine
kinase inhibitors (TKIs) has changed the outcome of this
Volume 15, Issue 2
 ALL in Older Adults
leukemia, at least in the short term. At present, it is actually
considered a favorable finding to have Ph-positive disease
among newly diagnosed older patients with ALL because it
offers a prospect of reasonably long survival.21 The finding
of Ph-positive disease and the striking single-agent activity
and excellent safety profile of TKIs have allowed the in-
corporation of TKIs into therapy and the de-escalation or
even complete elimination of some toxic agents.
The administration of TKIs early during induction therapy
improved the CR rate and lowered the induction mortality
rate in older patients with Ph-positive ALL.22 Given the
remarkable activity of TKIs in Ph-positive ALL, studies have
examined the role of maintaining chemotherapy backbone
intensity. In younger adults (, 60 years old), imatinib in
combination with vincristine and corticosteroids achieved a
superior CR rate and lower induction mortality rate com-
pared with imatinib in combination with hyperCVAD,
without impacting remission depth or long-term outcomes.
Both cohorts in this study received similar intensive cycles
of hyperCVAD after induction.23 Although imatinib in
combination with hyperCVAD induced a high CR rate, age
detrimentally influenced outcomes afterward, with a 5-year
OS rate of only 14% for patients older than age 60 years; in
addition, the majority of deaths were unrelated to relapse.24
In the UKALL14 trial, the addition of PEG-ASP during TKI-
based induction resulted in an unacceptable induction
mortality rate (42%), and this subsequently led to elimi-
nation of PEG-ASP from the Ph-positive cohort.18
Therefore, it seems safe and beneficial to reduce che-
motherapy backbone intensity in Ph-positive ALL when
a TKI is added, and this is necessary in older patients
with ALL to reduce treatment-related mortality. The Gruppo
Italiano Malattie Ematologiche dell’Adulto (GIMEMA)
LAL0201-B study treated older patients with newly di-
agnosed Ph-positive ALL with imatinib and a corticosteroid,
and all patients achieved CR with no reported induction
deaths.25 Similarly, the PETHEMA ALLOPH07 study treated
older patients with Ph-positive ALL with a corticosteroid,
imatinib, and vincristine, after which patients received
imatinib in combination with maintenance mercaptopu-
rine, vincristine, methotrexate, and prednisone (POMP).
This approach yielded encouraging results, with median OS
exceeding 3 years.21 Although CR rates for imatinib and
minimal chemotherapy regimens are high in older adults,
subsequent leukemia relapse is common, resulting in poor
long-term outcomes.
Second-generation TKIs have the advantage of higher
potency compared with imatinib. The combination of
dasatinib with hyperCVAD in newly diagnosed adults with
Ph-positive ALL (including patients . 60 years old) yielded
encouraging long-term remissions for all patients, but the
report did not specifically comment on how older patients
faired.26 The GIMEMA LAL1205 study treated adults (in-
cluding 12 who were . 60 years old) with Ph-positive
ALL with induction dasatinib in combination with a
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corticosteroid, and all patients achieved CR.27 The Euro-
pean Working Group on Adult ALL (EWALL) PH-01 study
treated older patients with Ph-positive ALL ($ 59 years old)
with dasatinib in combination with low-dose chemotherapy,
and 96% achieved CR, with a 5-year OS of 36%.28 Nilotinib
is another second-generation TKI that has demonstrated
safety and encouraging activity when combined with
chemotherapy in Ph-positive ALL,29,30 and patient age did
not impact outcomes.30
The T315I mutation is common at the time of relapse in Ph-
positive ALL, especially after treatment failure with front-line
dasatinib (70% to 75%),27,28 and it predicts resistance to
nilotinib and dasatinib. Ponatinib is a third-generation TKI
that is active across a broad spectrum of BCR-ABL fusion
gene mutations, including T315I.31 Ponatinib was com-
bined with hyperCVAD as first-line therapy for adults (in-
cluding 32% who were $ 60 years old) with newly
diagnosed Ph-positive ALL. The combination was highly
active, and all patients achieved complete cytogenetic
remission. Complete molecular remission was recorded in
78% of patients, and consolidation with allogeneic HCT did
not improve outcomes. Thrombotic events, infections, and
pancreatitis are the main concerns with ponatinib, and a
strategy was implemented to dose reduce ponatinib in deep
responders.32 The GIMEMA LAL1811 study reported pre-
liminary results of ponatinib in combination with a corti-
costeroid in unfit or elderly patients with untreated Ph-
positive ALL. At 24 weeks, 61% of responders attained
complete molecular response. This combination was well
tolerated with encouraging 1-year OS.33
Table 1 lists the outcomes of chemotherapy trials for older
adults with Ph-negative and Ph-positive ALL. The regimens
used are listed in Table 2.
Allogeneic HCT in Older Patients With ALL
Although historically allogeneic HCT had not been offered
to older patients with ALL, the introduction of reduced-
intensity conditioning has extended the application of this
curative modality to older patients. Ironically, reduced-
intensity conditioning allogeneic HCT may be better tol-
erated than combination chemotherapy administered with
curative intent in a subset of older patients with ALL.
Investigators from Europe analyzed outcomes of allogeneic
HCT in older adults with ALL ($ 60 years old) in first CR and
reported 3-year OS and leukemia-free survival rates of 42%
and 35%, respectively.35 Similarly, analysis from North
America in older adults with ALL (. 55 years old) showed
an encouraging 3-year OS rate of 38%.36 Nonrelapse
mortality for allogeneic HCT from matched donors was
approximately 25%.35,36 Recently, there has been in-
creased use of haploidentical HCT in patients who lack
matched donors. However, its role in older patients with
ALL is less clear because use of reduced-intensity condi-
tioning was associated with inferior results in this setting.37
69
 Aldoss, Forman, and Pullarkat

TABLE 1. Studies of ALL in Older Adults

No. of Patients
No. of Median Age CR Rate IM Rate Response, Receiving alloHCT
Study Patients TKI (years; range) (%) (%) OS EFS, or DFS (%)
Studies including both
Ph-positive and
Ph-negative ALL
HyperCVAD2 122 NR $ 60 84 10 20% at 5 years NR NR
MRC UKALL XII/ECOG 100 None 56 (55-65) 73 18 21% at 5 years 5-year EFS, NR
E29933 19%
Modified DFCI19 30 Imatinib 58 (51-72) 67 13 52% at 2 years 2-year DFS, 16 (53)
52%
Ph-negative ALL studies
CALGB 91114 41 None $ 60 77 17 17% at 3 years 3-year DFS, NR
19%
GMALL6 268 NA 67 (55-85) 76 18 23% at 5 years 5-year CCR, NR
32%
EWALL7 59 NA 65 (61-83) 76 7 24% at 3 years 3-year DFS, NR
19%
PETHEMA ALL-9617 33 NA 65 (56-77) 58 36 39% at 2 years 2-year DFS, NR
46%
GRAALL-SA134 60 NA 66 (55-80) 82 8 24% and 35% at 2-year EFS, NR
2 years 24% and
35%
PETHEMA ALL-OLD0720 56 NA 66 (56-79) 74 11 Median, Median DFS, NR
12.4 months 8 months
Ph-positive ALL studies
GMALL (randomly TKI: 28; Imatinib TKI: 66 (54-79); TKI: 96; TKI: 0; 42% at 2 years 2-year DFS, NR
assigned to no TKI: 27 no TKI: 68 no TKI: no 19%
chemotherapy with or (58-78) 50 TKI: 8
without imatinib during
induction)22
GIMEMA LAL0201-B25 29 Imatinib 69 (61-83) 100 0 74% at 1 year 1-year DFS, NR
48%
EWALL-PH-0128 71 Dasatinib 69 (59-83) 96 4 36% at 5 years 5-year EFS, 7 (10)
27%
EWALL-PH-0229 56 Nilotinib 65 (55-85) 87 2 NR NR 9 (16)
30
Korean study 90, includ- Nilotinib 47 (17-77) 91 9 72% at 2 years 2-year DFS, 57 (70)
ing 25 72%
$ 55
GIMEMA LAL120527 53, includ- Dasatinib 54 (18-77) 100 0 69% at 2 years 2-year DFS, 18
ing 12 51%
pts . 60
PETHEMA ALLOPH0721 53 Imatinib 66 (56-88) 87 13 Median, 37.3 months Median DFS, 3
38 months
HyperCVAD plus 54, includ- Imatinib 51 (17-84) 93 2 43% at 5 years for 5-year DFS, None for patients
imatinib24 ing 14 all patients, but 14% 43% . 60 years old
pts . 60 for patients . 60
years old
HyperCVAD plus 72, includ- Dasatinib 55 (21-80) 96 4 52% at 5 years 5-year EFS, 12 (17)
dasatinib26 ing 46 42%
pts . 60
HyperCVAD plus 37, includ- Ponatinib 51 (27-75) 100 0 80% at 2 years 2-year EFS, 9 (24)
ponatinib32 ing 12 81%
pts
$ 60
(continued on following page)

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 ALL in Older Adults

TABLE 1. Studies of ALL in Older Adults (continued)

No. of Patients
No. of Median Age CR Rate IM Rate Response, Receiving alloHCT
Study Patients TKI (years; range) (%) (%) OS EFS, or DFS (%)
33
GIMEMA LAL1811 42, includ- Ponatinib 68 (27-85) 91 0 88% at 1 year NR NR
ing 33
pts $ 60

Abbreviations: ALL, acute lymphoblastic leukemia; alloHCT, allogeneic hematopoietic cell transplantation; CALGB, Cancer and Leukemia Group B; CCR,
complete cytogenetic response; CR, complete remission; DFCI, Dana-Farber Cancer Institute; DFS, disease-free survival; ECOG, Eastern Cooperative
Oncology Group; EFS, event-free survival; EWALL, European Working Group on Adult Acute Lymphoblastic Leukemia; GIMEMA, Gruppo Italiano Malattie
Ematologiche dell’Adulto; GMALL, German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia; GRAALL, Group for Research on Adult Acute
Lymphoblastic Leukemia; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; IM, induction mortality; MRC,
Medical Research Council; NA, not applicable; NR, not reported; OS, overall survival; PETHEMA, Programa Español de Tratamientos en Hematologı́a; Ph,
Philadelphia chromosome; TKI, tyrosine kinase inhibitor; UKALL, United Kingdom Acute Lymphoblastic Leukaemia.

Therefore, allogeneic HCT can be recommended for older
patients with high-risk ALL (high-risk genetic features or
persistence of minimal residual disease) in first CR if the
patient is fit and has a matched donor. We often use allogeneic
HCT as consolidation therapy even in standard-risk patients,
particularly if adequate chemotherapy cannot be safely de-
livered. Arguably, allogeneic HCT is the only curative therapy
for relapsed patients if a subsequent CR is achieved and is
recommended for patients who remain fit to undergo HCT.
Relapsed and Refractory ALL
Older patients with relapsed or refractory ALL are unlikely to
gain benefit from additional conventional chemotherapy,
which carries substantial risk of life-threatening toxicity and
low chance of attaining CR. New immunotherapies and
targeted agents have shown encouraging activity in relapsed
or refractory ALL irrespective of age. However, it must be
mentioned that these agents can be toxic and expensive and
have limited curative potential as single agents. Table 3 lists
studies of novel agents in older patients with ALL.
Blinatumomab is a CD3 and CD19 bispecific antibody that
has shown remarkable activity in relapsed or refractory and
minimal residual disease (MRD)–positive ALL. Blinatu-
momab induced higher response and improved OS in
relapsed or refractory ALL compared with standard salvage
chemotherapy.43 Furthermore, blinatumomab induced a
high rate of MRD-negative responses (80%) among pa-
tients with relapsed or refractory MRD-positive ALL, and a
subset of patients enjoyed prolonged remissions afterward
without further therapy.44 The responses to blinatumomab
occurred irrespective of patient age (composite CR, 56% v
46% for patients $ and , 65 years old, respectively), with
no difference in OS or relapse-free survival based on age,
and the treatment was well tolerated in older adults except
for higher risk of neurotoxicity.40
Inotuzumab, a CD22 immunoconjugate, has produced
better response and OS rates compared with physicians’
choice of therapy in relapsed or refractory ALL.41 Age per
se did not influence response to inotuzumab (CR or CR
with incomplete blood count recovery, 70% v 75% for
patients , and $ 55 years old, respectively; P 5 .24);
however, older patients had lower median OS (5.6 v
8.6 months for patients $ and , 55 years old, respectively;
P 5 .0032).45 The main concern with inotuzumab treat-
ment is the risk of veno-occlusive disease, particularly in
patients who subsequently undergo allogeneic HCT.46
Furthermore, inotuzumab was combined with hyper-
fractionated reduced-dose cyclophosphamide, vincristine,
dexamethasone, cytarabine, and methotrexate in patients
with relapsed or refractory ALL with a median age of 35
years (range, 18 to 78 years), and the combination pro-
duced an encouraging high CR rate (78%), with 1-year OS
rate of 46%.47
Chimeric antigen receptor (CAR) T-cell therapy has
emerged as promising therapy in B-cell ALL. Although only
a few older patients have been treated in CAR T-cell
studies, response was not different based on patient age.
For the eight patients older than age 60 years treated on the
Memorial Sloan Kettering Cancer Center study, the CR rate
was 75%.42 Similarly, all four patients older than age 60
years treated on another CAR T-cell study achieved MRD-
negative CR.48
For patients with Ph-positive ALL who experience relapse
after imatinib, second-generation TKIs can induce second
remissions in a subset of patients. For patients who expe-
rience progression after a second-generation TKI, ponatinib
is active in subset of these patients.31 Furthermore, re-
sponses to blinatumomab, inotuzumab, and CAR T cells
have been observed in patients with relapsed or refractory
Ph-positive ALL, and these therapies are options for patients
who experience progression on TKI therapy.39,41,42
INTEGRATION OF NOVEL AGENTS INTO FRONT-LINE
THERAPY FOR OLDER ALL PATIENTS
There is mounting interest to introduce novel agents early in
the course of ALL treatment given their acceptable safety
profile and significant activity regardless of patient age.
Inotuzumab was successfully combined with reduced-dose
cyclophosphamide, dexamethasone, and methotrexate in
newly diagnosed older adults (median age, 68 years) with

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 Aldoss, Forman, and Pullarkat

TABLE 2. Published ALL Regimens in Older Adults

Regimen Induction Regimen Consolidation Regimen Use of ASP and Dose
HyperCVAD2 Fractionated CY, VCN, DOX, DEX Alternating cycles of CVAD 3 3 and None
HD-MTX 1 ara-C 3 4
GMALL6 Pre-P: DEX, CY, IT MTX Alternating ID-MTX (days 1 and Escherichia coli ASP (10,000 IU/m2) on
IND1: DEX, VCN, IDA 15) 3 3, VM-26/ara-C 3 2, reinduction days 2 and 16 of ID-MTX
IND2: CY, ara-C (VCN, IDA, CY, ara-C) 6 rituximab PEG-ASP (500 IU/m2) 3 1
EWALL and PETHEMA ALL- Pre-P: DEX, IT MTX Alternating ID-MTX 1 ASP 3 3, ASP 10,000 IU/m2 on day 2 3 3 doses
OLD077,20 IND1: DEX, VCN, IDA, ITT ID-ara-C 3 3
IND2: CY, ara-C, ITT
MRC UKALL XII/ECOG IND1: DAN, VCN, PRED, HD-MTX 1 ASP 3 3 ASP 10,000 IU/m2 3 10 doses during IND
E29933 ASP, IT MTX CON1: ara-C, VP16, VCN, DEX and 3 3 doses during HD-MTX
IND2: CY, ara-C, MP, IT MTX CON2: ara-C 1 VP16 3 2
CON3: IDA, CY, ara-C, TG
UKALL1418 PREP: DEX HD-MTX 1 ASP 3 3 PEG-ASP 1,000 IU/m2 on days 4 and
IND1: DAN, VCN, DEX, CON1: ara-C, VP16, VCN, DEX 18 of IND
PEG-ASP, IT MTX CON2: ara-C 1 VP16 3 2
IND2: CY, ara-C, MP, IT MTX CON3: IDA, CY, ara-C, TG
CALGB 91114 DAN, PRED, CY Stage IIA 1 IIB: CY, MP, ara-C, VCN, ASP 6,000 IU/m2 3 8 doses during course
ASP, IT MTX 2
Stage III: CI, IT MTX, MP, low-dose MTX
Stage IV: DOX, VCN, DEX, CY, TG, ara-C
PETHEMA ALL-9617 DAN, VCN, PRED, IT MTX CON1: MP, ID-MTX, VM-26, ara-C, ITT ASP during CON at 10,000 IU/m2 3 6
(ASP, CY)* CON2: DEX, VCN, CY, ASP, ITT doses and during reinduction cycles at
Reinduction: VCN, PRED, ASP, ITT 20,000 IU/m2 3 1
monthly during first year
Modified DFCI19 PRED, VCN, DOX, PEG-ASP, IT CON1: Clofarabine, PRED, PEG-ASP PEG-ASP 500 IU/m2 during IND and
MTX, IT ara-C CNS: VCN, DOX, MP, DEX, PEG-ASP, ITT CON 3 6 doses total
CON2: VCN, DOX, MP, DEX,
PEG-ASP 3 8 cycles
GRAALL SA134 PREP: PRED, IT MTX CON1: DOX, VCN, DEX None
IND1: DOX, VCN, DEX CON2: CY, ara-C, MP
IND2: CY, DOX, VCN, DEX CON3: DOX, VCN, DEX
CON4: CY, ara-C, MP

Abbreviations: ALL, acute lymphoblastic leukemia; ara-C, cytarabine; ASP, asparaginase; CALGB, Cancer and Leukemia Group B; CI, cranial irradiation;
CON, consolidation; CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; CY, cyclophosphamide; DAN, daunorubicin; DEX,
dexamethasone; DFCI, Dana-Farber Cancer Institute; DOX, doxorubicin; ECOG, Eastern Cooperative Oncology Group; EWALL, European Working Group on
Adult Acute Lymphoblastic Leukemia; GMALL, German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia; GRAALL, Group for Research on
Adult Acute Lymphoblastic Leukemia; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; HD, high dose; ID,
intermediate dose; IDA, idarubicin; IND, induction; IT, intrathecal; ITT, triple intrathecal chemotherapy; MP, mercaptopurine; MRC, Medical Research
Council; MTX, methotrexate; PEG, pegylated; PETHEMA, Programa Español de Tratamientos en Hematologı́a; PRED, prednisone; PREP, preparation; Pre-P,
prophase; TG, thioguanine; UKALL, United Kingdom Acute Lymphoblastic Leukaemia; VCN, vincristine; VM-26, teniposide; VP16, etoposide.
*Omitted on updated cohort.

Ph-negative ALL. The combination was shown to be safe,
with no induction mortality, and the composite CR rate was
as high as 98%, including 96% of patients who became
MRD negative in the first 3 months of therapy. The com-
bination resulted in an encouraging 3-year OS rate of
56%,38 which seems more favorable compared with the
standard hyperCVAD regimen in this setting, which pro-
duced a 5-year OS rate of only 20%.2 Inotuzumab is
currently being tested in combination with chemotherapy
in the EWALL-INO study (ClinicalTrials.gov identifier:
NCT03249870).
Blinatumomab has been combined safely with TKIs in
advanced Ph-positive leukemias, including in eight patients
receiving ponatinib, and responses were encouraging.49
Blinatumomab is being studied as front-line therapy
for newly diagnosed older patients with Ph-positive and
Ph-negative ALL in combination with TKIs and POMP
maintenance by SWOG (ClinicalTrials.gov identifier:
NCT02143414). The GIMEMA LAL2116 study is testing
front-line dasatinib and corticosteroids in adults (no age
limit) with newly diagnosed Ph-positive ALL, followed by
consolidation with blinatumomab (ClinicalTrials.gov iden-
tifier: NCT02744768). Ponatinib in combination with bli-
natumomab in older adults with Ph-positive ALL is also
being investigated (ClinicalTrials.gov identifier: NCT03263572
and EWALL-PH-03).

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 ALL in Older Adults

TABLE 3. Trials of Novel Therapies in Older Patients With ALL

No. of Patients
No. of Median Age CR Rate Receiving
Therapy Patients Ph Status Setting (years; range) (%) MRD (%) OS PFS or RFS alloHCT (%)
Inotuzumab 1 52 Negative Newly diagnosed 68 (64-72) 98 78* 56% at 3-year PFS, 3 (6)
mini-hyperCVD38 3 years 49%
Blinatumomab in 23 ($ 55 Positive Relapsed/ $ 55 35 86† NR Median RFS, 2 (25)
Ph-positive ALL39 years old) refractory 6.7 months
Blinatumomab phase II40 36 ($ 65 Negative Relapsed/ 70 (65-79) 56 60 Median, 5.5 Median RFS, 3 (15)
years old) refractory months 7.4 months
Inotuzumab phase III41 60 ($ 55 Positive and Relapsed/ 65 (55-78) 70 79 Median, 5.6 Median PFS, 17 (28)
years old) negative refractory months 4.9 months
MSKCC CD19 CAR 8 Positive and Relapsed/ . 60 75 67† NR NR NR
T cells42 negative refractory

Abbreviations: ALL, acute lymphoblastic leukemia; alloHCT, allogeneic hematopoietic cell transplantation; CAR, chimeric antigen receptor; CR, complete
remission; mini-hyperCVD, hyperfractionated reduced-dose cyclophosphamide, dexamethasone, and methotrexate; MRD, minimal residual disease;
MSKCC, Memorial Sloan Kettering Cancer Center; NR, not reported; OS, overall survival; PFS, progression-free survival; Ph, Philadelphia chromosome; RFS,
relapse-free survival.
*MRD at the time of morphologic remission, but this was as high as 96% any time during the first 3 months.
†MRD for all patients. No MRD response was specified in the article for older patients.

OUR APPROACH still recommend allogeneic HCT even if MRD negativity is

Whenever possible, we try to enroll older patients with ALL
onto clinical trials given the disappointing results of con-
ventional chemotherapy. Outside of clinical trials, we treat
older patients with Ph-negative ALL with a three-drug in-
duction regimen (daunorubicin, vincristine, and a corti-
costeroid) if the performance status is reasonable and
cardiac function is preserved.21,34 We avoid ASP in older
patients because of the high risk of toxicity, which can
contribute to induction mortality as well as delay sub-
sequent treatment cycles.7,17,18
For older patients with good early response to induction
therapy (MRD negative), with adequate performance status
without high-risk genetics, or who are not candidates for
allogeneic HCT, we consider continuing therapy with a
modified pediatric-type regimen that includes alternating
cycles of nonmyelosuppressive agents incorporating low-
dose PEG-ASP to maximize chance of cure. After consol-
idation, we give 2 years of POMP maintenance. If the
patient achieves morphologic CR but remains MRD positive
after induction, we recommend consolidation with blina-
tumomab given its high response rate for MRD, low toxicity,
and reasonable chance of long-term remission, even
without allogeneic HCT. However, for fit older patients, we
achieved with blinatumomab, but the value of this ap-
proach is debatable.44
If an older adult is refractory to initial therapy, our prefer-
ence is to enroll the patient onto a clinical trial. If ineligible
for a clinical trial, we administer blinatumomab if the patient
is fit and eligible for HCT given the safety of blinatumomab
in this setting. However, if allogenic HCT is not an option,
we choose between blinatumomab and inotuzumab based
on different factors such as the presence of extramedullary
disease, which has been shown to predict low response
to blinatumomab,50 or the presence of hepatic disease,
which would increase risk of veno-occlusive disease with
inotuzumab.
For Ph-positive ALL, we recommend induction therapy with
a TKI in combination with a corticosteroid with or without
vincristine. We prefer dasatinib because of its higher po-
tency and better CNS penetration. We still consider allo-
geneic HCT in suitable older adults with Ph-positive ALL
who attain first or subsequent CR. For older adults with
T-cell ALL, we maximize our efforts to optimize their front-
line regimens because relapsed or refractory T-cell ALL at
any age carries a dismal prognosis with limited salvage
treatment options.

AFFILIATION Center, City of Hope National Medical Center, Duarte, CA;

1
Gehr Family Leukemia Research Center, City of Hope National Medical e-mail: vpullarkat@coh.org.
Center, Duarte, CA
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
AND DATA AVAILABILITY STATEMENT
CORRESPONDING AUTHOR
Disclosures provided by the authors and data availability statement (if
Vinod Pullarkat, MD, MRCP, Department of Hematology and
applicable) are available with this article at DOI https://doi.org/10.1200/
Hematopoietic Cell Transplantation, Gehr Family Leukemia Research
JOP.18.00271.

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 Aldoss, Forman, and Pullarkat

AUTHOR CONTRIBUTIONS Manuscript writing: All authors

Conception and design: All authors Final approval of manuscript: All authors
Data analysis and interpretation: All authors Accountable for all aspects of the work: All authors

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n n n

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 Aldoss, Forman, and Pullarkat

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Acute Lymphoblastic Leukemia in the Older Adult
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held
unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about
ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jop/site/ifc/journal-policies.html.

Ibrahim Aldoss Vinod Pullarkat

Speakers’ Bureau: Jazz Pharmaceuticals Consulting or Advisory Role: Novartis, Amgen, Pfizer, Jazz Pharmaceuticals
Speakers’ Bureau: Novartis, Amgen, Jazz Pharmaceuticals, Shire
Stephen J. Forman
Patents, Royalties, Other Intellectual Property: Mustang Bio

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