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Curr Hematol Malig Rep. Author manuscript; available in PMC 2021 December 01.
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Published in final edited form as:

Curr Hematol Malig Rep. 2020 December ; 15(6): 424–435. doi:10.1007/s11899-020-00597-y.

New approaches to treating challenging subtypes of ALL in AYA

patients
Kevin Prescott, MD1, Michael Jacobs, MD1, Wendy Stock, MD1, Joseph Wynne, MD, PhD1
1Department of Medicine, University of Chicago Medicine, Chicago, IL, USA

Abstract
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Purpose of Review: The treatment of acute lymphoblastic leukemia (ALL) in adolescent and
young adult (AYA) patients has markedly improved with the adoption of pediatric-inspired
protocols. However, there remain several subtypes of ALL that represent significant therapeutic
challenges. Here, we review the current evidence guiding treatment of Philadelphia chromosome
positive (Ph+), Philadelphia chromosome-like (Ph-L), and Early T precursor (ETP) ALL in the
AYA population.

Recent Findings: Clinical trials in Ph+ ALL have demonstrated the superior efficacy of second
and third generation tyrosine kinase inhibitors (TKIs) to induce and maintain remission. Current
efforts now focus on determining the durability of these remissions and which patients will benefit
from transplant. For Ph-like and ETP ALL, recent studies are investigating the addition of novel
agents to standard treatment.
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Summary: The treatment of Ph+ ALL has significantly improved with the addition of potent
TKIs. However, the treatment of Ph-like and ETP ALL remains a challenge. At this time, the
judicious use of allogenic transplant is the only current approach to modify this increased risk.

Keywords
ALL; AYA; ETP; Ph-like; Ph+ ALL

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Corresponding author: Joseph Wynne, Address: Knapp Center for Biomedical Discovery, 900 E. 57th Street, 8th Floor Chicago,
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Illinois 60637, USA, joseph.wynne@uchospitals.edu, Phone: 773-702-4400, Fax: 773-834-0778.

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been
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up to date and so may therefore differ from this version.
Conflicts of Interest
Dr. Prescott has nothing to disclose.
Dr. Jacobs has nothing to disclose.
Dr. Stock reports personal fees from AMGEN, personal fees from ABBVIE, personal fees from PFIZER, personal fees from JAZZ,
personal fees from ADAPTIVE BIOTECHNOLOGIES, during the conduct of the study; personal fees from ASTELLAS, personal
fees from UP TO DATE, outside the submitted work; .
Dr. Wynne reports personal fees from Servier, outside the submitted work.
Human and Animal Rights and Informed Consent All reported studies/experiments with human or animal subjects performed by
the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and
its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
 Prescott et al. Page 2

Introduction
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It is well known that outcomes for acute lymphoblastic leukemia (ALL) worsen with age.
Moreover this worrisome trend has a significant inflection point in adolescence, where risk
of relapse significantly increases compared to younger peers [1]. Survival rates in children
with ALL are upwards of 80%, while the historical survival rate in adults is almost half of
this, at roughly 40%. Over the last decade, dramatic improvements in this survival rate have
been made in large part because of a paradigm shift in the treatment of young adults and
adolescents (AYA) with ALL, with a new focus on treatment using pediatric-inspired
chemotherapy regimens that rely on higher overall doses of steroids, vinka alkaloids,
asparaginase, and intensive central nervous system (CNS) prophylaxis. Numerous studies
have shown that by administering these regimens to patients up to 40 years of age, survival
rates in this population can approach those of the pediatric population. This shift in
treatment strategy for the AYA population was highlighted in a 2018 review in JAMA
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Oncology by Siegel, et al, which revealed that 23 of 25 comparison studies assessing

outcomes between pediatric and adult regimens for AYAs with ALL, in addition to one
meta-analysis, favor the pediatric regimen [1]. While the majority of studies included in this
review are retrospective, more recent prospective trials have further strengthened this
approach. In one of these trials Deangelo, et al applied a pediatric-based chemotherapy
regimen to 92 patients with ALL aged 18-50 to investigate tolerability of a 30-week
asparaginase course previously shown to be associated with favorable outcomes in children.
They found that 72% of patients who initiated the asparaginase course were able to tolerate
26 or more doses, which was similar to what the group had reported in pediatric populations.
Furthermore, the 67% 4-year overall survival (OS) rate seen in their patient cohort was
favorable compared to historical survival rates in adults [2]. A subsequent trial by the
NOPHO group applied a common pediatric-inspired treatment protocol to 1500 patients
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aged 1-45 stratified into risk groups to determine safety and efficacy of their pediatric-
inspired chemotherapy regimen. Despite worse outcomes in the adolescent and adult
subgroups compared with pediatric patients, their reported 4-year event free survival of 74%
+- 4% in patients aged 18-45 still compared favorably to survival rates previously reported
in adult patients on traditional adult regimens [3]. Most recently, Stock, et al reported the
CALGB 10403 trial that prospectively compared a pediatric regimen used in 295 ALL
patients aged 17-39 to historical controls enrolled in prior CALGB adult trials. Median
event-free survival in this group was 78.1 months, more than double the historical control of
30 months [4]. Importantly, these dramatic improvements in survival come at a time when
the incidence of ALL is growing faster in this age distribution than in the pediatric and adult
populations [1].
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The improved outcomes using pediatric-inspired chemotherapy regimens do not come

without cost. These treatments feature high cumulative doses of steroids, traditional
chemotherapy agents, and in particular, asparaginase. Incorporation of asparaginase, an
agent that had been used in the treatment of pediatric ALL for decades, into the treatment of
adults with ALL has contributed substantially to improved outcomes, but carries with it
unique toxicities. It has been found to cause more hepatic dysfunction, pancreatitis, and
coagulopathies in AYA patients compared to children. A few patients can also experience

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serious hypersensitivity reactions [5]. However, the recent large prospective trials discussed
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above showed significantly favorable benefit to toxicity ratios for the use of their
asparaginase-containing regimens. Deangelo, et al demonstrated that a similar percentage of
AYA patients were able to tolerate a 30-week asparaginase course compared to children [2].
Although CALGB 10403 did witness higher incidence of hepatic and thrombotic
complications during induction therapy compared to younger pediatric patients treated with
a similar protocol, toxicities during post remission cycles in its AYA cohort were comparable
to those reported in the pediatric population [4]. Fortunately, there are studies that suggest
reduced doses of asparaginase may be feasible in attaining therapeutic activity levels while
limiting treatment-altering toxicity [6]. Nevertheless, learning how to identify asparaginase
toxicity and to manage it is a particular apprehension for oncologists treating ALL in an
AYA patient who may not be as familiar with its effects.

One of the reasons posited for the historically lower survival rates in the AYA and adult ALL
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populations is the increased prevalence of resistant ALL subtypes as patients age. The
heterogenous biologic nature of the disease affects outcomes and presents treatment
challenges. The two immunophenotypes of the disease, precursor B-cell and precursor T-cell
ALL, have different treatment approaches in risk-adapted regimens, with T-cell regimens
often employing more intensive CNS prophylaxis. The incidence of T-cell ALL increases
with age into adolescence and young adulthood, and although post-induction complete
remission rates in AYAs with T-cell ALL approximate those with B-cell ALL, those who
relapse with T-ALL tend to have worse outcomes [4]. Moreover, recently identified subsets
necessitate further individualization of treatment approach based on their higher rates of
treatment resistance. Within T-cell ALL, early T-cell precursor ALL (ETP ALL) is one
subset that was initially identified due to its unique immunophenotype and poor outcomes.
Additionally, Philadelphia Chromosome-like ALL (Ph-L ALL) has emerged as a relatively
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common variant of B-cell ALL particularly in the AYA age group and has proven to be more
resistant to standard treatment regimens. For example, in the CALGB 10403 trial, 31% of
evaluable patients were identified as having Ph-like fusions and these patients’ estimated 3-
year event-free survival of 42% compared poorly to the 69% event-free survival (EFS) for
patients without the Ph-like signature. Finally, Philadelphia-chromosome positive ALL (Ph+
ALL) accounts for up to 30% of ALL in adults and has historically had a poor prognosis
with standard treatment. However, outcomes have been improving with the addition of novel
tyrosine kinase inhibitors (TKI) to treatment regimens. These three variants of ALL will be
discussed further below, with particular consideration given to their management in AYA
patients.

While the majority of ALL patients will reach complete remission (CR) following induction
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chemotherapy, a significant number relapse, likely due to the presence of leukemic cells
below the detection limits of microscopy. Newer methods of analysis (flow cytometry, next
generation sequencing) that can identify this level of disease, termed minimal residual
disease (MRD), have greatly added to our understanding of treatment response and risk of
relapse. Regardless of the genetic makeup of the disease, it has become increasingly
apparent that the achievement of undetectable MRD during the course of treatment predicts
a better outcome. This was most clearly demonstrated in a 2017 meta-analysis that pooled
39 publications of >13000 adult and pediatric patients with ALL. The study showed an

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estimated 10-year event-free survival for pediatric patients achieving MRD negativity of
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77% compared with 32% for patients who did not achieve MRD negativity. For the adult
studies, those who achieved MRD negativity had a 64% EFS at 10 years compared with only
21% in those who were MRD-positive [7]. It should be noted that none of the studies
included in the meta-analysis were strictly investigating this effect in the AYA population.
However, similar results were seen in the previously mentioned CALGB AYA trial—the 3-
year disease-free survival for patients in this trial achieving MRD negativity was 85% versus
only 54% for those with detectable MRD. This relationship between MRD status and
prognosis is integral to pediatric risk-adjusted regimens, where patients receive escalation of
therapy if found to be MRD positive at the end of induction. Additionally, there are ongoing
efforts to specifically target MRD to prevent relapse and improve survival. As an example,
blinatumomab, a bispecific T cell-engager antibody that directs T cells to CD19+ B cells,
has now been approved by the Food and Drug Administration to treat adults with B-cell
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ALL that are MRD-positive [8].

Lastly, one must appreciate various psychosocial challenges that add additional complexity
to the management of ALL in the AYA population. AYA patients must endure a long
duration of intense treatment at a time in their lives that, in normal circumstances, would be
dedicated to one’s personal and professional development. The rigorous regimens almost
always necessitate leaves of absence from school or work which can cause significant
financial burdens, delay academic or career achievements, disrupt family life or the ability to
find life partners, result in chronic health complications, and leave many survivors with
psychologic trauma. Additionally, whereas in the pediatric population patients are often
surrounded by family members who can administer medications, provide transportation to
appointments, and generally take active roles in the patient’s treatment, AYAs often must
navigate their disease with far less support. Some have posited that this independence has
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contributed negatively to treatment adherence and thus can contribute to the lower survival
rates in the AYA population [9]. As a result of these complexities, a multi-disciplinary
approach featuring among others psychologists, nutritionists, fertility experts, and social
work is crucial to the successful treatment of these patients [10].

Featured here is a review of the current literature surrounding treatment approaches for AYA
patients with the following high risk ALL subsets: ETP ALL, Ph+ ALL, and Ph-L ALL.

Early T-Cell Precursor Acute Lymphoblastic Leukemia (ETP ALL):

ETP ALL is a high-risk subset of T-cell ALL that compromises roughly 15% of T-ALL
cases and is defined by a specific genetic profile: CD1a−, CD8−, CD5weak, & 1 or more
myeloid/stem cell marker [11-14]. Early T-cell precursors are early thymic immigrants from
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bone marrow that retain the ability to differentiate into T-cell and myeloid lineages. Thus,
the genetic features of ETP-ALL often straddle that of acute myeloid leukemia (AML) and
ALL, and many cases harbor mutations traditionally seen in AML [12, 15, 16]. Individuals
with ETP ALL have higher rates FLT3 & DNMT3A mutations, with lower rates of NOTCH
mutations (which has been shown to be associated with a good prognosis), compared to non-
ETP T-ALL cases [17, 18, 15, 19-21]. These cells have increased genomic instability, and

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some researchers have hypothesized that their myeloid characteristics result in poor response
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to traditional T-ALL directed chemotherapy [15, 12, 22].

Data on the outcome of patients with ETP ALL is conflicting, but in many series, these
patients have an adverse treatment response and outcome compared to other subsets of T-
ALL. Individuals with ETP ALL have decreased response to prednisone, earlier
development of drug resistance, and higher rates of failed induction therapy, MRD positivity
at the end of induction, and relapse [22, 13, 17, 14]. While initial studies found this disease
to confer a poor prognosis, several more recent studies have shown that response-based risk
stratification and subsequent therapy intensification can overcome this initially described
poor prognosis [23-25]. In the pediatric population, separate studies by Patrick et al. and
Sayed et al. found non-inferior outcomes among ETP cases; Patrick et al. showed a 5 year
OS of 82.4% vs 90.1%, while Sayed et al. showed 5 year OS of 70.8% vs 76.6% in ETP vs
non-ETP cases – neither being statistically significant. Both studies attribute this to the more
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intensive therapy administered to the ETP groups [25, 24]. In the adult population, Bond et
al. found that the use of allogeneic stem cell transplant (SCT) in first complete remission
(CR1) could overcome the high-risk features of ETP ALL. While individuals with ETP had
higher rates of corticosteroid resistance, early bone marrow chemotherapy resistance, and
higher rates of MRD positivity post-induction, there was no statistical difference in EFS or
OS when compared to non-ETP cases (5 year OS 59.6% vs 66.5%). This was attributed to
the increased frequency of alloSCT in ETP patients (48.9% vs 28.3%) as a result of initial
treatment resistance (defined by the study as corticosteroid resistance, early bone marrow
chemotherapy resistance, and failure of remission induction), suggesting alloSCT in CR1
based on risk stratification can overcome the effect of early treatment resistance seen in ETP
ALL. This study also suggests induction augmentation and therapy intensification alone may
be insufficient for successful management of ETP ALL; without transplant, ETP cases had
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lower OS than non-ETP cases (49.2% vs 67.5%) and there was a trend toward improved OS
with alloSCT for ETP ALL patients (hazard ratio 0.36, p=0.07), but not for non-ETP
patients (hazard ratio 0.7, p=0.36) [23]. An important caveat of this study is the lack of
complete MRD data, thus preventing analysis of whether SCT improved outcomes in ETP
patients who achieved complete molecular remission. A multi-center analysis of SCT in T-
ALL by Brammer et al. further supports the use of SCT in ETP ALL. Although limited by
sample size (16 total ETP patients), these researchers found no statistically significant
difference in OS between ETP and non-ETP patients who underwent SCT (47% vs 63%,
p=0.5), again highlighting that alloSCT in CR1 may overcome the high-risk features and
previously described poor outcomes of ETP ALL (see table 1).

Currently, the European Society for Blood and Marrow Transplantation recommends SCT in
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CR1 for adults with ETP, but not for children with ETP [26, 20, 27]. This becomes a grayer
area for the AYA population, and the treatment of these patients is variable – some receiving
traditional pediatric regimens, others receiving a less intensive version of a pediatric
backbone, and others receiving the hyper-CVAD regimen [28, 26, 29, 30]. Our general
approach is to pursue SCT in CR1 for AYA patients with ETP if they are good candidates for
transplantation and have slower clearance of MRD; however, this may not be appropriate in
cases where MRD clears within 12-16 weeks of initiation of treatment of an intensive
pediatric regimen. This is based not only on the high-risk features/high relapse rates of ETP-

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ALL and previous success demonstrated with therapy intensification and SCT, but also the
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limited options and poor prognosis for relapsed T-ALL cases. Currently nelarabine is the
only approved treatment for relapsed T-ALL, and relapsed T-ALL patients fare far worse
than relapsed B-ALL individuals [31, 32].

There is promising pre-clinical data for future treatments of ETP ALL. Ruxolitinib has been
shown efficacious regardless of JAK mutation status in in-vitro studies – importantly, there
is a high rate of JAK/STAT alterations in ETP cases [18, 21]. Currently there is a clinical
trial investigating Ruxolitinib in patients with relapsed/refractory ETP-ALL
(NCT03613428). As with JAK/STAT alterations, there is a high rate of PIM1 overexpression
in ETP cases and pre-clinical research has shown the combination of PIM inhibitors with
ponatinib improved survival and decreased tumor burden in ETP mouse models [33]. Other
individuals have proposed incorporating traditional AML agents into the treatment of ETP
ALL – chemotherapy regimens using high dose cytarabine have been shown effective in
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certain cases [15, 12]. Additional options include the targeting of apoptotic pathways; a trial
investigating venetoclax + navitoclax for the treatment of refractory/relapsed T-ALL is
currently underway. Phase I data, while limited by sample size, shows promise – with a
response rate of 56% [34].

Philadelphia Chromosome-Positive ALL (Ph+ ALL):

The management and outcomes for Ph+ ALL have dramatically changed with the
development of tyrosine kinase inhibitors (TKIs). Prior to their development, the prognosis
for Ph+ ALL was dismal, with long term OS <25% in adult populations and <50% in
pediatric populations [35, 36]. With the introduction of TKIs, survival rates have greatly
improved [26, 37, 38]. Historically, SCT was the only curative approach to treatment of Ph+
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ALL cases [39-41]. Now, with the introduction of potent TKIs, the universal need for SCT in
AYA patients with Ph+ ALL is less certain. A recent study by Ravandi et al. demonstrated
improved relapse-free survival (RFS) and OS in young adults who received dasatinib +
chemotherapy with a recommendation to proceed to alloSCT in CR1. In this study, 44 of 94
eligible patients achieved CR and did not undergo HCT. Landmark analysis was performed
at 175 days after achieving CR as this was the longest time from achieving CR to
undergoing HCT. The 3-year RFS for these patients after this landmark date was 51% and
OS was 56%. For the 41 patients who did undergo HCT in CR1, the 3-year RFS was 76%.
Importantly, this study included adults up to the age of 60 years (not limited to AYAs) and
used a relatively low dose of dasatinib in combination with intensive chemotherapy (70mg
daily after a protocol amendment). While the study was not randomized, it demonstrated
statistically significant improvement in RFS and OS for those patients who proceeded to
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alloSCT in CR1 (P=.038 for RFS, P=.037 for OS) [42].

The guidelines for SCT differ between adult and pediatric patients. In the pediatric
population, SCT is no longer the standard of care for standard risk cases in CR1 as it has
been found that TKI + chemotherapy is non-inferior to SCT [35, 43, 44, 27]. In contrast,
SCT is currently recommended in CR1 for adults with Ph+ ALL – provided they can tolerate
SCT and have a suitable donor [43, 45, 27]. These conflicting guidelines make it difficult to
provide definitive recommendations for the AYA population. Based on past trials

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demonstrating survival benefit for patients undergoing SCT, many experts in the field
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recommend SCT in CR1 for AYA patients with Ph+ ALL, especially for young adults with
no comorbidities and a suitable donor [41, 29, 43, 37, 38, 45, 46]. If SCT does occur, TKI
maintenance post-transplant should occur, provided it can be tolerated by the patient [27,
40].

With the development and continued investigation of newer TKIs, the new targeted
antibodies, and sensitive sequential quantitative MRD monitoring, the recommendation for
alloSCT in CR1 may evolve. Most of the data supporting SCT in CR1 is based on trials from
the pre-TKI era [29, 37]. Depending on the TKI tested, there is conflicting evidence for the
use of SCT in CR1. Several studies using imatinib showed a survival benefit for alloSCT in
CR1, however, more recent studies using newer generation TKIs suggest alloSCT in CR1
may not be indicated in standard risk patients [38, 45, 47, 29, 37, 48, 36]. One such study by
Chang et al. showed comparable results for dasatinib + chemotherapy with or without the
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SCT [36]. Evolving data suggests newer TKIs are superior to the first generation TKI
imatinib [41, 37, 40]. A recent combined study from China and St Jude’s Children Research
Hospital Showed superior results when using dasatinib over imatinib [49]. This is the first
randomized trial comparing different generation TKIs to each other – an important caveat,
however, is this study was performed in a strictly pediatric population (age <18). A MDACC
phase II trial on ponatinib + hyper-CVAD demonstrated high rates of long-term survival
with the use of this 3rd generation TKI. Furthermore, no difference in survival was seen
when comparing those who underwent SCT to those who did not – 3 year OS 87% in the
non-transplant group vs 70% in the alloSCT group [50]. Continued investigation into newer
TKIs and their ability avoid SCT is essential moving forward. The morbidity and mortality
associated with SCT should not be understated, and the ultimate goal should be to develop
regimens that obviate the need for SCT – a large percentage of transplant patients will suffer
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from chronic graft versus host disease (cGVHD) and SCT-related mortality remains ~20% in
AYA patients with ALL [51, 52, 46, 48]. As with the pediatric population, it is possible that
SCT in the AYA population will be eventually be reserved for those who fail to achieve CR
after 30 days of therapy or who have persistent MRD [26].

Regardless of whether SCT occurs, it is likely that patients should undergo combined
chemotherapy + TKI; new studies may also demonstrate feasibility of TKI and targeted
antibody treatments with minimal chemotherapy. Traditionally, it was recommended patients
receive high intensity chemotherapy, including the hyper-CVAD and BFM-like regimens.
Now, however, there are data supporting the use of lower intensity chemotherapy with a
second generation TKI as a means of inducing remission in patients who subsequently
undergo SCT [53, 48, 37, 46]. With the introduction of the new targeted immune therapies,
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there are trials currently underway investigating the use of reduced intensity treatments
without subsequent transplant. Initial results from an Italian study (NCT02744768) looking
into dasatinib + blinatumomab in adults with Ph+ ALL shows promise – with reported 1
year OS of 94.2% (see table 2) [54].

Lastly, MRD monitoring and targeting is an essential component for the management of Ph+
ALL, as MRD is the major driver for relapse risk [55-57]. While SCT can convert MRD
positivity, the outcomes for patients who are MRD+ pre-transplant are significantly worse

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than those who are MRD- at the time of transplant [46]. Growing evidence on the impact of
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MRD targeting suggests SCT may not be needed in cases with early achievement of MRD
negativity [37, 41, 58]. The overall trend for the management of Ph+ ALL seems to be the
use of newer generation TKIs with risk modeled SCT via MRD and molecular resistance
monitoring.

Philadelphia Chromosome-Like ALL:

Philadelphia Chromosome-like ALL (Ph-L ALL) is a recently described heterogeneous
subset of ALL, with a similar gene expression profile to Ph+ ALL, but lacks the
characteristic BCR-ABL1 fusion from t[9;22] [59-61]. As with Ph+ ALL, this disease subset
is characterized by kinase activations – the majority being JAK/STAT pathway alterations
and ABL class fusions – that drive its development [62-66]. Ph-L ALL occurs most
frequently in the AYA population, comprising 20-30% of B-cell precursor ALL in this age
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group and the vast majority of these patients have translocations that result in CRLF2 and/or
JAK activation [62, 59, 67, 68]. Patients with Ph-L ALL respond poorly to conventional
chemotherapy with elevated rates of induction failure, higher rates of post-induction MRD
positivity, and higher relapse rates compared to non-Ph-L cases. Initial studies on this
disease subset have shown significantly decreased OS and EFS when compared to other
types of B-ALL (excluding Ph+ ALL) [69-71]. Currently, neither a standard diagnostic nor a
standard treatment approach exists. However, since many cases contain potentially targetable
kinase rearrangements, there is significant research into the efficacy of various TKIs in Ph-L
ALL.

At this point in time, the most important step is identifying patients with Ph-L ALL. There
are several proposed methods and diagnostic algorithms for doing so, and this topic is
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largely beyond the scope of this review. At the University of Chicago Medical Center we use
a stepwise approach that focuses first on detection CRFL2 overexpression (seen in 50% of
Ph-L ALL cases) by flow cytometry, followed by the use of a Ph-L specific Fluorescence In
Situ Hybridization (FISH) panel aimed to capture the most commonly seen fusions in Ph-L
ALL [70, 65, 59, 72]. Alternatives to this include the use of Ph-L specific low-density arrays
(LDA) as an initial screening method, although these LDAs are not currently commercially
available [73, 60]. The ultimate hope is that RNA-sequencing will become available and
feasible, as this will allow for comprehensive detection of this disease subset [74, 60].

In regards to treatment, pre-clinical data on JAK inhibitors and ABL inhibitors have been
promising [75-77, 68]. Whether or not this will translate to clinical results remains to be
seen, but there are several case reports demonstrating the success of TKIs in Ph-L ALL and
several trials investigating TKI use in Ph-L ALL are currently underway (NCT02883049;
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NCT03564470; NCT03571321; NCT02420717) [78, 65, 73, 79-83]. Alternative strategies to

the use of TKIs, such as inotuzumab or blinatumomab, are also being investigated
(NCT03150693; NCT02003222) (see table 3). Given the lack of guidelines in managing Ph-
L ALL at this time, we recommend newly diagnosed cases of Ph-L ALL be referred to
clinical trials [30].

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The role of MRD-based risk stratification and SCT is less clear in Ph-L ALL cases [84, 85].
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While some studies have shown that risk-directed therapy based on MRD can overcome the
poor prognosis of Ph-L ALL, other studies have shown poor outcomes regardless of MRD
status and risk-stratification in this disease subset [86-88, 84]. Specifically, a study at
MDACC by Jain et al. found poor outcomes regardless of MRD status, with median OS of
26 months and 23 months in MRD- and MRD+ groups, respectively [71]. Similarly, Heatley
et al. found poor outcomes and high relapse rate despite MRD risk-stratification – yet they
suggest SCT can salvage some cases [88]. In contrast, Roberts et al. found the poor
prognosis of Ph-L ALL can be salvaged with MRD-based risk-directed therapy – with a
non-significant 5 year OS of 92.5% vs 95.1% in the Ph-L group vs non-Ph-L group [86].
Our current approach at the University Chicago Medical Center is as follows: we
recommend referring Ph-L ALL patients to clinical trial, but if there is any signs of
inadequate response – induction failure or persistent MRD positivity – we then use novel the
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novel agents blinatumomab or inotuzumab with the purpose of achieving MRD negativity
and then following this with alloSCT for suitable candidates. We do not take MRD negative
patients in CR1 directly to transplant. This approach will evolve with the continued
development of target therapies and novel agents.

Local Practice Pattern

At the University of Chicago AYA program, we struggle to implement some of these diverse
data points but proceed as follows. Patients that present with ETP ALL are treated per
CALGB 10403 through at least consolidation while we search for suitable transplant donors.
If a suitable donor is available, we strongly recommend the patient proceed with allogeneic
transplant. If a donor is unavailable, we complete treatment per the CALBG 10403 protocol.
At this time, we have not incorporated nelarabine into the treatment of these patients.
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Patients that present with newly diagnosed Ph+ ALL undergo induction with a combination
of dasatinib and dexamethasone following the CALGB 10701 protocol. We discuss
transplant if a suitable donor is available. If a donor is not available or if the patient is not
interested in transplant, we proceed with a methotrexate course for CNS prophylaxis
followed by a maintenance course with continued TKI. Lastly, patients with Ph-L ALL are
enrolled on the Alliance A041501 trial, which was recently amended to include treatment
with blinatumomab for persistent MRD. If the patient fails to achieve CR, fails to clear
MRD, or relapses, we treat as relapsed ALL and proceed with allogenic transplant if a donor
is available.

Conclusions
The treatment of all subtypes of ALL in the AYA patient population has significantly
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improved over the last decade. However, the high-risk subtypes of ETP ALL, Ph+ ALL, and
Ph-L ALL continue to pose substantial therapeutic challenges in the clinic. While there has
been great improvement in Ph+ ALL with the addition of potent TKIs to treatment regimens,
studies in the AYA patients remain conflicted about who will benefit from alloSCT. Clinical
trials to investigate ETP ALL and Ph-L ALL are ongoing with the hope that either novel
immune-based or molecularly targeted therapies will improve upon existing treatment
backbones. It is hoped that upon the completion of these trials the field will have tailored

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regimens for these high-risk subtypes and will determine who will best benefit from alloSCT
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as a standard component of their treatment plan.

Acknowledgments
KP and MJ have no acknowledgements for this work.

WS has no acknowledgements for this work.

JW is supported by 5K12CA139160-10

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Table 1.

Previous Studies on ETP ALL. EFS = Event Free Survival. OS = Overall Survival. HR = Hazard Ratio. CR =
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Complete Remission. Cri = Complete Remission with incomplete count recovery. CR1 = First Complete
Remission

Study ALL Age Overview Results Takeaways

subtype (ETP ALL vs
other T-ALL)
Coustan- T-ALL 0.5-18 Comparison of outcomes 10-year OS 19% vs 85%, 10- Early study demonstrating poor
Smith et al.13 between ETP-ALL and T- year EFS 22% vs 69% outcomes with standard
ALL in pediatric population (p<0.0001) intensive chemotherapy in
using standard intensive pediatric population.
chemotherapy.

Inukai et al.14 T-ALL 1-18 Comparison of outcomes of 4-year EFS 40% vs 70% Higher rates of relapse in ETP
ETP-ALL and T-ALL in a group. Data limited by sample
pediatric population size (N=5 for ETP).

Allen et al.11 T-ALL 1-81 Comparison of outcomes of Statistically higher relapse OS analysis limited by sample
(median ETP-ALL and T-ALL rates in children (HR=11.63, size (N=7 for ETP). Higher
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13) p=0.025), but not for all age relapse rates in pediatric
groups (HR=4.08, p=0.127) population.

Jain et al.17 T-ALL 13-79 Comparison of outcomes
(median between ETP-ALL and other
30) T-ALL. Induction therapy
consisted of hyper-CVAD or
augmented-BFM. Routine
alloSCT in CR1 not done.
CR/CRi rates were 73% vs Suggests ETP-ALL is a high-
91% (p=0.03). Median OS 20 risk subset of T-ALL, with
months vs not reached worse outcomes when using
(p=0.008). conventional chemotherapy.

Patrick et al. T-ALL 1-24 Comparison of outcomes of Non-significantly inferior 5- High risk features of ETP-ALL
24 ETP-ALL and T-ALL treated year EFS and OS (76.7% vs may be overcome with risk-
with the UKALL 2003 84.6%, 82.4% vs 90.9%). stratified treatment
protocol intensification

Sayed et al.25 T-ALL 1-18 Comparison of outcomes of In the group treated with the High risk features of ETP-ALL
subsets of T-ALL treated with Total Therapy Study XIII may be overcome with risk-
different protocols protocol for high-risk ALL stratified treatment
there was a non-significantly intensification
inferior outcome for ETP:
70.8% vs 76.6% (p=0.67)
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Bond et al.23 T-ALL Adults Comparison of outcomes of Non-significantly inferior 5- AlloSCT in CR1 may overcome
(median ETP-ALL vs other T-ALL in year EFS and OS (59.6% vs the early treatment resistance
age 31.5) adults using early response- 66.5%). Without transplant and high-risk features of ETP-
based intensification ETP cases had inferior 5-year ALL
strategies OS (49.2% vs 67.5%, p=
0.02)

Brammer et T-ALL 2-72 Comparison of T-ALL Non-significantly 3-year OS AlloSCT in CR1 may overcome
al.31 (median subtypes and MRD on after SCT in CR1 (47% vs the early treatment resistance
31) alloSCT outcomes 65%, p=0.5) and high-risk features of ETP-
ALL. Study limited by sample
size: total of 16 ETP patients,
with 10 undergoing alloSCT in
CR1.
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Table 2.

Previous Studies on Ph+ ALL. EFS = Event Free Survival. OS = Overall Survival. HR = Hazard Ratio. CR1 =
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First Complete Remission. CMR = Complete Molecular Response.

ALL
Study Age Overview Results Takeaways
Subtype

Shen et al.49 Ph+ ALL 0-18 Comparison of dasatinib Significant improvement in 4- Newer generation TKIs may
to imatinib in treatment of year EFS and OS between prove more effective in
Ph+ ALL in pediatric dasatinib vs imatinib groups: 71 treatment of Ph+ ALL when
population % vs 48.9% (p=0.005) & 88.4% compared to first generation
vs 69.2% (p=0.04) TKIs

Chang et al.36 Ph+ ALL 18-70 Comparison of outcomes Similar outcomes between the With newer generation TKIs,
for adult Ph+ ALL transplant and non-transplant routine alloSCT in CR1 may
patients treated with group: 3-year OS 76% vs 71.3% not be indicated
combination (p=0.56), 3-year RFS 70.5% vs
chemotherapy + dasatinib 80.1% (p=0.94)
vs combination
chemotherapy + dasatinib
followed by alloSCT
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Jabbour et al.50 Ph+ ALL >18 Phase II trial of ponatinib Good long-term outcomes: 83% Ponatinib + combination
(median + hyper-CVAD in achieved CMR, 3-year OS 76%. chemotherapy leads to good
47) treatment of adult Ph+ No improvement in survival with long-term outcomes, and
ALL alloSCT: 3-year OS in transplant may avoid need for routine
group vs non-transplant group alloSCT in CR1
was 70% vs 87%.

Ravandi et al.42 Ph+ ALL 18-60 Outcomes of adult
patients with Ph+ ALL
treated with dasatinib +
combination
chemotherapy followed
by alloSCT
3-year RFS in patients who did
NOT undergo SCT in CR1 (44
pts) was 51%; 3-year RFS for
those who did undergo alloSCT
in CR1 was 76%; statistically
significant improvement in RFS
and OS for pts who underwent
SCT vs no SCT (NOT
randomized however)
Addition of dasatinib to
chemo and alloSCT for
younger patients with Ph+
ALL is feasible and
efficacious. Patients fared
better if they received
alloSCT, however the study
was not randomized and thus
warrants further testing.

≥18 Outcomes of patients Initial results show a 1-year OS Addition of blinatumomab to

treated with dasatinib + of 94.2% TKI therapy may allow
NCT02744768 Ph+ ALL
blinatumomab avoidance of intensive
chemotherapy
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Table 3.

Current trials on treatment of Ph-L ALL and novel agents for B-ALL. Ph-L ALL = Philadelphia-chromosome
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like ALL. B-ALL = B-cell precursor ALL. HR = high risk. R/R = relapsed/refractory. TKI= tyrosine kinase
inhibitor. HDACi = histone deacetylase inhibitor

Trial ALL Subtype Age Overview

(years)
NCT02883049 HR B-ALL and Ph-L 1-30 Phase III randomized trial of combination chemotherapy for newly diagnosed HR B-
ALL ALL. Includes a stratum of patients with Ph-L ALL and a predicted TKI-sensitive
mutation treated with dasatinib + combination chemotherapy

NCT03564470 Ph-L ALL 14-55 Evaluation of the safety and effect of the HDACi chidamide and dasatinib in Ph-L ALL

NCT03571321 Ph-L ALL 18-39 Phase I trial on ruxolitinib + pediatric-based chemotherapy regimen in AYAs with Ph-L
ALL

NCT02420717 R/R Ph-L ALL 10+ Phase II trial comparing ruxolitinib with chemotherapy to dasatinib with chemotherapy
in patients with R/R Ph-L ALL

NCT03150693 B-ALL 18-39 Phase III trial assessing efficacy of inotuzumab + frontline therapy in AYAs with newly
diagnosed B-ALL
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NCT02003222 B-ALL 30-70 Phase III trial comparing combination chemotherapy with blinatumomab to
chemotherapy alone in adults with newly diagnosed BCR-ABL negative B-ALL
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