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Philadelphia-Like Acute Lymphoblastic Leukemia: A Systematic Review

Vineeta Yadav, Prasanth Ganesan, Raveendranath Veeramani, Dinesh Kumar V

PII: S2152-2650(20)30426-2
DOI: https://doi.org/10.1016/j.clml.2020.08.011
Reference: CLML 1668

To appear in: Clinical Lymphoma, Myeloma and Leukemia

Received Date: 19 June 2020

Revised Date: 9 August 2020
Accepted Date: 10 August 2020

Please cite this article as: Yadav V, Ganesan P, Veeramani R, Kumar V D, Philadelphia-Like Acute
Lymphoblastic Leukemia: A Systematic Review, Clinical Lymphoma, Myeloma and Leukemia (2020),
doi: https://doi.org/10.1016/j.clml.2020.08.011.

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Title: Philadelphia-Like Acute Lymphoblastic Leukemia: A Systematic Review

• Author names and affiliations:

Vineeta Yadav1; Prasanth Ganesan2; Raveendranath Veeramani3; Dinesh Kumar V4

1
Department of Anatomy, Jawaharlal Institute of Postgraduate Medical Education and
Research, Puducherry, India 605006 vini009.vy@gmail.com
2
Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education
and Research, Puducherry, India 605006. pg1980@gmail.com
3
Department of Anatomy, Jawaharlal Institute of Postgraduate Medical Education and
Research, Puducherry, India 605006. dr_raveendra@rediffmail.com

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4
Department of Anatomy, Jawaharlal Institute of Postgraduate Medical Education and

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Research, Pondicherry, India 605006. dinesh.88560@gmail.com

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• Corresponding author: Raveendranath Veeramani
Department of Anatomy, Jawaharlal Institute of Postgraduate Medical Education and
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Research, Puducherry, India 605006. email: dr_raveendra@rediffmail.com

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Conflict of interest: There is no conflict of interest

Abstract: Philadelphia-Like Acute Lymphoblastic Leukaemia (Ph-like ALL) is a subgroup
of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) with a gene expression
profile analogous to Philadelphia-positive Acute Lymphoblastic Leukemia (ALL) and
recurrent IKAROS Family Zinc Finger 1 (IKZF1) gene deletion despite lacking BCR-ABL1
(Breakpoint cluster region-ABL protooncogene) translocation. Though recognized to occur at
all ages, the proportion of cases among BCP-ALL varies (<10% in children and up to 30% in
adolescents). In all age groups, males are more commonly affected. Generally Ph-like ALL is
associated with adverse clinical features and increased risk of treatment failure with
conventional approaches. Genetic alterations such as aberrant expression, point mutations, or

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fusion translocations lead to activation of cytokine receptors and signaling kinases, which

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affect the ABL1(ABL class fusion) or Janus Kinase (JAK) signaling pathways. Several clinical
trials are being conducted to understand whether specific Tyrosine Kinase Inhibitor (TKI)
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therapy can improve cure rates. This review summarizes the current literature available about
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this entity.
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Keywords: Acute lymphoblastic leukemia, Philadelphia chromosome, Philadelphia-like,

BCR-ABL1, CRLF2, interleukin-7 receptor, Janus kinase 2, IKZF1, IKAROS
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Introduction:
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Acute lymphoblastic leukemia (ALL) is the commonest malignancy in the pediatric

population accounting for 25% of cancers diagnosed in them (1). It is characterized by the
accumulation of malignant, immature lymphoid progenitor cells in the bone marrow,
peripheral blood, and other sites such as lymph node, spleen, liver, and central nervous
system (1). Based on their origin from stem cell/progenitor cells, two common subtypes can
be classified namely: B lineage ALL (B ALL) and T lineage ALL (T ALL) (1).
Recently, a new subgroup of B-ALL has been identified with a gene expression profile (GEP)
that is similar to Ph-positive ALL but with a myriad group of genetic alterations. This entity,
however, lacks the t(9;22) translocation or the BCR-ABL fusion, and hence named as “Ph-
like” ALL or “BCR-ABL-like” ALL (2). These cases are frequently associated with the
deletion of IKZF1. It has been reported by the previous studies that this particular subgroup is
also associated with inferior outcome, adverse clinical feature and treatment failure identical
to Ph-positive ALL (3)
We conducted a systematic review to understand the incidence, distinctive clinical features,
associated gene signatures of Ph-like ALL, and the outcomes of these patients with current
treatment.

Methods:
Data origins and findings
For this review article, the investigators collected articles written in English from
databases such as PubMed and Google Scholar published from 2000 to 2019. The search for
articles was done from 15th March 2019 to 20th May 2019. To fine-tune the search, keywords
such as “B-ALL”, “Acute lymphoblastic leukemia”, “BCR-ABL1”, “CRLF2”, “interleukin-7
receptor”, “Janus kinase 2”, “Philadelphia like ALL”, “IKZF1”, “IKAROS” and “MRD”

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were used. Papers were carefully assessed and classified based on inclusion and exclusion

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criteria. The citations for all databases were specified. This study was conducted based on the

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preferred reporting items for systematic reviews in PRISMA format.
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Selection criteria and data extraction
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Studies of ALL that were either prospective or retrospective with the primary
outcomes of our interest (incidence, diagnostic approach, prognostic impact, and several
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associated gene signatures of Ph-like ALL) were chosen. Data for the secondary outcome of
interest, that is treatment targets of Ph-like ALL patients were extracted and reported for
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additional analysis.
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The following studies were excluded- 1) Study of leukemia other than B-ALL, 2) lack
of description about Ph-like ALL diagnosis incidence, treatment outcome, survival rate, and
3) poor description of the applied methods.

Results

Search outcome:
The search process was concluded by analyzing abstracts of those articles fulfilling
the inclusion criteria with primary and secondary outcomes. Then the patient’s sample,
sample size, population ethnicity, methodology and, technical procedures were recorded. The
initial evaluation resulted in the identification of 127 articles related to Acute lymphoblastic
leukemia. Out of these 127 articles, 78 were excluded and 50 were selected for full-length
review. 31 articles that lacked information related to baseline characteristics parameters were
eliminated from the study in the second round of selection process.
 In the next stage, the selected articles were classified based on the incidence,
distinctive clinical features, several associated gene signatures of Ph-like ALL and, their
treatment protocols. The extracted information included the type of study, sample size, major
findings, MRD (minimal residual disease) status, and survival outcome in both children and
adolescent young adult patients (AYA). The selection process is depicted in the form of a
PRISMA flow diagram [Figure-2]. The incidence and outcomes are tabulated based on the
age group and method of analysis in Table 1. Table 2 contains the treatment outcomes in the
three age groups studied in various clinical trials. Table 3 contains a description of altered
kinase genes detected in Ph-like ALL.

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Baseline characteristics of included studies

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As seen in Table-4, accumulation of 19 included studies rendered us the dataset of

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12973 ALL and 1744 Ph-like ALL patients. The median age of the patients in these studies
ranged from 5.3 to 40 years and median white blood cell count ranged from 7.1 to
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92.7x109/L. The methods used to diagnose the Ph-like ALL cases in these studies were
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predominantly Prediction Analysis for Microarrays (PAM) of an Affymetrix gene expression

array based on 257 gene probe set, which was used in 11 studies (3–13). Three studies used
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the Hierarchical Clustering of an Affymetrix gene expression array based on a probe set of
110 genes (2,14,15). One study used the Xenograft model (16).
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Discussion

Molecular Characterization of Ph-Like ALL:

Philadelphia-like ALL has diversified genomic outlook in wide comprehensive

genomic profiling studies, presenting with multiple rearrangements, copy number alterations
and, sequencing which leads to activation of tyrosine kinase or cytokine receptor signaling
pathways (4,5,17). So far, 60 rearrangements in 15 kinase or cytokine receptor genes have
been documented. (3–5,17). Based on the activation of tyrosine kinase and cytokine receptor
signaling pathway, these alterations can be categorized as 6 confined sub-groups. These
include CRLF2 overexpression, IKZF deletions, ABL-class genes uniting, JAK2 or EPOR
rearrangements or fusions, JAK-STAT, or MAPK pathways activation, and other rare
variations.
• CRLF2 displacement: The CRLF2 gene is spotted at chromosome XP22.3/YP111.3, which
encodes the Cytokine receptor-like factor 2 (Thymic stromal lymphopoietin receptor).
Rearrangement of CRLF2 accounts for 42-60% of Ph-like ALL in the 10-39 years age
group (4). It was reported that along with mutation of the JAK family, CRLF2
overexpression was constitutively present. However, CRLF2 overexpression is more
commonly associated with JAK2 when compared to JAK1 and JAK3 (6,18). Elevated
CRLF2 expression also results from cryptic deletion and translocation with the P2RY8-
CRLF2 in young children and IGH-CRLF2 in young adults. (19) Overexpression of CRLF2
in B-ALL is also stimulated by gain-of-function mutations which could either be CRLF2
itself or its partner gene, IL7RA. (19)

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• IKZF deletions: IKAROS zinc finger family transcription factors is a protein encoded by the

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IKZF gene. It plays a very important role in the development and maturation of lymphoid
progenitors (20,21). IKZF deletions with certain non-coding single nucleotide
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polymorphism makes it prone to develop B-lineage ALL (22). This deletion is common in
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B-ALL with or without the BCR-ABL translocation. (23,24) It is seen in 15-30% in BCR-
ABL negative ALL and 60% in BCR-ABL positive ALL (25,26). The deletion is also
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established as a poor prognostic factor in both high risk and standard-risk patients in all the
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age groups (29,30). In terms of pathogenic events, it disturbs normal B cell differentiation
and triggers uncontrolled leukemic cell proliferation. It has a unique adhesive property
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which aggravates the cell division. The adhesive power of IKZF leads to leukemogenesis
and aberrant adhesion of leukemic cells to bone marrow recess. These leukemic cells
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provide resistance to tyrosine kinase inhibitors, which may be counteracted by retinoic acid
compounds and FAK inhibitors. Due to this mechanism, Ph-like ALL shows inferior
outcomes and poorer prognosis (24,27,28).
• ABL class rearrangements: One of the most important subtype accounting for 10% of Ph-
like ALL. It occurs 17% in children, 9% in adolescent, 10% in young adults, and 9% in
older adults (4,5,17). ABL-class activates signaling pathways which mediate the
pathophysiology of Ph-like ALL. This group includes kinases ABL1, ABL2, PDGFRA,
CSF1R, PDGFRB, and LYN. (9) Patients with translocations particularly PDGFRB have
shown induction failure. As an adjunct to the conventional chemotherapy, TKI inhibitors
such as imatinib and dasatinib are commonly used in order to down-regulate the
manifestations of translocations (4).
• JAK2-STAT signaling/EPOR rearrangements: Half of the patients of Ph-like ALL with
CRLF2 rearrangement have concomitant activating mutation of Janus Kinase gene, JAK1
and JAK2 which leads to activation of JAK-STAT signaling pathway (6,29,30). The
frequency of JAK mutations in adults with CRLF2 rearrangement is lower with JAK wild
type which is 1:4 (5). There are several other gene-based phenomena which cause JAK-
STAT signal activations. It can be JAK mutations with or without, JAK2 fusions, EPOR
rearrangement encoding the erythropoietin receptor, and rarely involves IL7R, SH2B3, and
others (4,5,17). The independent rearrangements of JAK2 and EPOR occur in
approximately 7% and 5% cases of Ph-like ALL respectively. So far 20 different JAK2
fusions have been recognized which makes it the most heterogeneous gene in Ph-like ALL.

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Four different types of EPOR rearrangements have been identified. JAK inhibitors

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Ruxolitinib can be a productive therapy that targets the EPOR/JAK rearrangements and
other activating mutations (13,31,32).
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Few rare kinase driven mutations are also found in the genomic profile of the Ph-like ALL
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which involves BLNK, NTRK3, TYK2, PTK2B, FGFR1, etc. FLT3 mutation is most
common in high risk ALL(4,5,17). ETV6-NTRK3 (tropomyosin receptor kinase) a rare but
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repeated mutation defined 1% of Ph-like ALL(33). However, the oncogenic role of ETV6-
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NTRK3 in B-ALL is not yet established. It has been identified in only one study, conducted
in the conditional knock-in-mouse model, that activation of ETV6-NTRK3 using CD19-Cre
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could result in the rapid development of pre-B ALL with complete penetrance and
infiltration of leukemic blasts into multiple organs, including bone marrow, spleen, and the
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central nervous system. (33). An efficient treatment with TRK inhibitor larotrectinib
decreases the burden to some extent. (34)
• In addition, there are other genes such as KRAS, NRAS, NF1, PTPN11, etc. which can cause
mutations in the RAS pathway. Such deficiency is found in 4% of Ph-like patients.
Deviations in this pathway are frequently seen with MLL rearrangement. MEK inhibitors are
considered as a novel therapeutic route for Ph-like ALL with RAS mutations(4,5,17). ETV6-
NTRK3 fusion is one of the indications of activated RAS pathway. The fusion has been
diagnosed in various types of malignancies, such as secretory breast carcinoma, congenital
fibrosarcoma, and pediatric pontine glioma. TRK inhibitors such as Larotrectinib and ALK
inhibitors Crizotinib are currently being used as target therapy. (35)

Incidence:
 As reported in Table-1, the incidence of Ph-like ALL varies with age in different
studies. In Adolescent and Young Adults, it ranges from 18% to 42% (4,5,7,9,11,15,17). and
in children, it is 13% (4) and in older individuals, it is 7-25% (5,9,11,15).
The highest incidence was reported by Gene Expression Profile in the 15-39 year age
group. Other techniques like flow cytometry, fluorescent in-situ hybridization and,
sequencing have reported an uneven range from 18-27% (9,11). Study with new techniques
such as Affymetrix U133 Plus Version 2.0 gene expression microarray and Affymetrix SNP
Version 6.0 microarray profiling, Sanger sequencing using Prediction analysis of microarray
reported Ph-like ALL in 14% of the patients (7).
The incidence may vary depending upon the type of tests which is used to detect or

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define Ph-like ALL. Most of the multicentric studies applied gene expression profiling using

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either U133 Plus 2.0 microarrays or low-density array [LDA] as a diagnostic tool for Ph-like
ALL and reported with high incidence (4,7,9).
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Diagnosis of Ph-like ALL
As seen in Table 1, different studies have used an array of techniques for defining Ph-
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like ALL. In the updated WHO 2016 classification, BCR-ABL like B-lymphoblastic leukemia
/lymphoma is defined as “a neoplasm of lymphoblasts committed to the B-cell lineage that
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lack the BCR-ABL1 translocations but showing a pattern of gene expression very similar to
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that seen in ALL with BCR-ABL1”.

However, current clinical definition has tried to identify this entity using tools
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like FISH, FCM, and PCR as these are more applicable in practice. Using these techniques
different algorithms have been developed to try and define the Ph-like ALL (6). Techniques
like gene expression profile/Next-generation sequencing may not be routinely available for
clinical use in many settings. As flow cytometry is routinely available, quick, low cost and
reliable technique it has been commonly used to detect CRLF2 overexpression in the
diagnostic panel. The higher expression of CRLF2 is more commonly associated with its
rearrangement in Ph -ve adult patients. Metaphase FISH was also performed to identify the
rearrangements including CRLF2-IGH, CRLF2-P2RY8, and it had shown 100 %
concordance with the results of MFC (Multiparameter flow cytometry). (19)

It has been reported in previous studies that CRLF2 overexpression and

rearrangement are commonly accompanied by JAK1/JAK2 mutation and IKZF1 deletions (6).
Real-time quantitative Polymerase chain reaction (Q-PCR) was performed to assess CRLF2
overexpression (18). P2RY8-CRLF2 transcript was identified by RT-PCR. JAK mutation was
examined by PCR amplification and sanger sequencing. IKZF1 deletion was detected by
Multiplex ligation-dependent probe amplification (MLPA) (18).

With respect of the identification of cryptic translocations and MRD sensitive

markers, the RT-PCR technique has emerged as a gold standard diagnostic tool over
conventional cytogenetics (36). RT-PCR assay was developed to detect specific gene fusion
by using a panel of individual monoplex assay. The tedious procedure of detecting leukemia
gene profile using individual monoplex assay is eased out following the utility of Multiplex
RT-PCR, especially when we need to evaluate multiple leukemia translocations in the same
specimen(37).

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In a few clinical trials, the researchers performed quantitative RT-PCR-based low-

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density array (LDA) to assess CRLF2 expression and rearrangements and subsequently for
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kinase alterations. To confirm CRLF2 rearrangement and other JAK1, JAK2, and IL7R
mutations Sanger Sequencing technique was also used. This way of investigation is tiring and
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cumbersome but advantageous for a large number of patients in multicentric studies. (19)
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DNA and RNA-based sequencing such as whole genome, whole exome, and whole-
transcriptome sequencing are the most comprehensive techniques to examine single
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nucleotide variants, structural and copy number variation, which provides adequate
information about Ph-like ALL.
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Prognostic impact
Although several kinds of treatment protocols are available for different age groups
for Ph-like ALL. As seen in table-2 it has been observed in previous studies that the survival
outcome in children was in the range from 15-94%. The highest survival in pediatric ALL, as
per St. Jude study, is 90% and yet it is lower compared to Ph-like ALL. In other age groups
i.e. adolescents, young adults, and older adults survival outcomes ranged from 13.6% to
34.6% (3,4,6). This difference arises despite adopting similar treatment strategies in a few
studies.
Similar to age, there are various prognostic factors such as Gender, Ethnicity, White
blood cell count at diagnosis (of greater than 30,000/L (B-ALL)), Central nervous system
involvement, Morphological, Immunophenotype, Minimal residual disease status and Genetic
Abnormalities responsible for adverse clinical profile and inferior outcomes. It has been
reported that elevated MRD level is frequently associated in all the age group with high-risk
B-ALL subtype.(17,38) These factors play a crucial role in risk stratification. Such risk
stratification and exact evaluation of prognosis is a focal point of treatment management (39).
The prognostic impact of MRD was also observed in the study conducted at St. Jude
research center. Risk directed strategy was followed to measure MRD levels during remission
induction therapy. There was no significant difference reported in inferior event-free survival
between Ph-like and other subtypes of B-ALL. However, significantly higher level of MRD
was more likely detected in Ph-like ALL, classified as a high-risk group, and received
haematologic stem cell transplantation (HSCT) for further treatment (3).

Treatment targets

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As discussed in previous sections, conventional chemotherapy produces poor

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outcomes in Ph-like ALL. Hence there is a need for developing newer approaches. As seen in
Table-3 although there is extensive genetic heterogeneity, ABL and JAK-STAT mutations are
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the most commonly involved genes that can be targeted for therapy (Table 3). This table
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shows various treatment targets in Ph-like ALL.
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ABL targeted pathway: Patients presenting ABL class rearrangements are around 10-15%
(17% of children, 9% of adolescents, 10% young adults, and 9% older adults) with Ph-like
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ALL (4,5,17). There are approximately 12 gene fusions in this cohort which are targeted with
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ABL1 inhibitor, Imatinib, and the dual ABL1/SRC inhibitor, Dasatinib by inhibiting the
downstream signaling induced by each of these chimeric fusion proteins both in-vitro and in-
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vivo (4,13,32). Remarkable results were observed with particular group PDGFRB, which is
known for the adverse outcome (38,40–42). In clinical trial AALL1131, the COG is under
investigation to assess the competence of Dasatinib in newly identified National Cancer
Institute defined high-risk patients. Accustomed augmented BFM based chemotherapy is
combined with Dasatinib from starting of consolidation to maintenance therapy. (43)

JAK-STAT signaling targeted pathway:

The result of activation of the JAK-STAT signaling pathway coincides with the
number of gene aberrations involving with or without JAK-STAT mutation, CRLF2, EPOR
and other minor IL7R, SH2B3 rearrangements (44). Among these, JAK1/JAK2 inhibitor
ruxolitinib, has been identified as a most effective against JAK-STAT–activating alterations
(JAK1, JAK2, JAK3, IL7R, IL2RB), but not TYK2. (32). In combination with
dexamethasone, type 2 JAK inhibitors also provide an adequate response. Based on their
functional mechanism type 2 JAK inhibitors are found to serve as a potent target strategy for
those with CRLF2 rearrangements. (45,46)
Although ABL1-class and JAK-STAT alterations account for the majority of Ph-like
ALL cases targeted by TKI inhibitors, there are several other alterations involving kinases
that are neither inhibited by ABL-class nor JAK inhibitors [e.g. BLNK, NTRK3, and TYK2]
(32). It was observed that the activation of these kinases also contributes to B-ALL disease
progression. There are various TRK targeting inhibitors such as Entrectinib and Larotrectinib,
which provides impressive and robust impact in-vitro and in-vivo treatment. (33) 75% overall
response out of 55 patients was reported in 3 studies which were conducted using
Larotrectinib. (46)

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At the end of induction and during the early consolidation period, the finding of

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higher MRD levels emphasizes inferior outcome in Ph-like ALL. Other than several
treatment strategies depending upon specifically targeted molecule, recently, immunotherapy
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has gained significance. It has a combination of monoclonal antibodies including
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Blinatumomab, Inotuzumab, and CAR-T cells, which offers promising alternative approach
wherein CD19 +ve cells by Blinatumomab, CD 22 +ve cells by Inotuzumab, and both the
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positive CD cells is lysed by CAR-T cells, which stimulate the immune system after binding
in B-ALL cases (47,48).
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As reported in previous studies, chemotherapy followed by allogeneic hematopoietic

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stem-cell transplantation (alloHSCT) has improvised the survival outcome in B-ALL with
BCR-ABL translocations and patients with MRD positive (47,49). However, for BCR-ABL
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like ALL, the data to demonstrate the effect of allogeneic hematopoietic stem-cell
transplantation (alloHSCT) in outcome is still not available.

Conclusion
The evidence and results obtained from preclinical studies would play a great role in
the future treatment approach for Ph-like ALL. The success of combinatorial treatment of
TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may
similarly improve outcomes in patients diagnosed with Ph-like ALL. To date, no ideal
therapy has been defined for relapse-free survival. Although various research studies and
trials are still under-process to find therapeutic strategies for these patients, there is potential
for further research and clinical trials which would enable us to understand the complexity of
the disease. There is also a need to formulate an approach for identifying the genetic
modifications responsible for the disease and diagnostic approaches at the earliest.
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Table 1
Frequency and outcomes of Ph-like ALL in children, adolescents and adults

Study Age Total no of No of Ph- Frequency Diagnostic

(years) B-ALL like Ph-like approach
Jain et al.(9) 15–39 80 33 42% Gene expression

of
40–84 68 16 24% profile, FISH

ro
Herold et al. 16–20 26 5 19% Gene expression
(11) profile, FISH
21–39 68 -p 12 18%
40–55 45 4 9%
re
55–84 67 5 7%
Boer et al. (15) 16–20 24 6 25% Gene expression
lP

21–39 48 9 19% signature

40–71 55 6 11%
Roberts et al. 21–39 344 96 28% Genomic Profiling
na

(5) Transcriptome
40–59 304 62 20% Sequencing
ur

60–86 150 36 24%

Roberts et al. 1–15 853 108 13% Next-Generation
Jo

(4) Sequencing
16–20 372 77 21% Microarray
21–39 168 46 27% Profiling and
Cytogenetic Assays
Loh et al. (7) 1–31 572 81 14% Gene expression
profiles
Reshmi et al. 1–31 1389 284 20% Gene expression
(17) profile

Table-2

I. Treatment outcome of Philadelphia like in pediatric

Clinical Trial Age(years) Risk Ph-like ALL Treatment Outcome

Group No.
Prevalence (%)
P9906 1–18 high-risk 31 68 5-yr EFS 25.9% ± 10%
Mullighan et al
(24)
COALL 92/97 0–18 all 19 28 5-yr DFS 59.5%
Den Boer et al
(2)
DCOG-ALL- 0–18 all 15 10 5-yr DFS 57.1%
8/9 Den Boer et
al (2)
AALL0232 1–18 high-risk 14 81 5-yr EFS 62.6% ± 6.9%
Loh et al (7)
DCOG-ALL- 1–18 all 16 94 5-yr CIR 32%
8/9/10
Vander Veer et
al (14)

of
Multiple trials 1–15 standard- 10 33 — —

ro
risk
Roberts et al 1–15 high-risk 12.7 108 5-yr EFS 58.2% ± 5.3%
(4)
-p
re
Roberts et al 16–20 all 20.6 77 5-yr EFS 41.0% ± 7.4%
(4)
lP

St. Jude Total 1–18 all 11.6 40 5-yr EFS 90.0% ± 4.7%
XV Roberts et
na

al (3)

II. Treatment outcome of Philadelphia like in adolescent and young adults

ur

Roberts et al 21–39 all 27.4 46 5-yr EFS 24.1% ±

Jo

(4) 10.5%
University 18–39 all 25.9 7 — —
Pennsylvania
Tasian et al (6)

Multiple trials 21–39 all 27.9 96 5-yr EFS 24.1%

Roberts et al
(3)

III. Treatment outcome of Philadelphia like in older adults

Roberts et al 21–39 all 27.4 46 5-yr EFS 24.1% ±

(4) 10.5%
University 18–39 all 25.9 7 — —
Pennsylvania
Tasian et al (6)
Multiple trials 21–39 all 27.9 96 5-yr EFS 24.1%
Roberts et al
(3)

Table 3
Kinase alterations in Ph-like ALL

Class Incidence Kinase Number Fusion partner genes Potential TKI

(50) gene of
fusion
partners
ABL Children- ABL1 12 CENPC, ETV6, FOXP1, Dasatinib
16.7% LSM14, NUP214,
NUP153, RCSD1,

of
Adolescen ANBP2, SNX2,
t(16-21 SFPQ, SPTAN1, ZMIZ1

ro
yrs)-9% ABL2 3 PAG1, RCSD1, ZC3HAV1 Dasatinib
CSF1R 3 MEF2D, SSBP2, Dasatinib
Young
adult(21- LYN 2
-p TBL1XR1
NCOR1, GATAD2A Dasatinib
re
39 yrs)- PDGFRA 1 FIP1L1 Dasatinib
10.4% PDGFRB 7 ATF7IP, EBF1, ETV6, Dasatinib
lP

SSBP2, TNIP1,
Adult (40- ZEB2, ZMYND8
86 yrs)-
na

9.2%
JAK-STAT Children- CRLF2 2 IGH, P2RY8 JAK inhibitor
24.1% PI3K/mTOR
ur

inhibitor
Adolescen
Jo

JAK2 20 ATF7IP, BCR, EBF1, JAK inhibitor

t(16-21 ETV6, PI3K/mTOR
yrs)-32% GOLGA5, HMBOX1, inhibitor
OFD1,
Young PAX5, PCM1, PPFIBP1,
adult(21- RFX3, SMU1, SNX29,
39 yrs)- SSBP2, STRN3, TERF2,
14.6% TPR, USP25, ZNF274,
ZBTB46,
Adult (40- EPOR 4 IGH, IGK, LAIR1, THADA JAK inhibitor
86 yrs)-
11.2% TYK2 3 MYB, SMARCA4, ZNF340 TYK2 inhibitor

IL2RB 1 MYH9 JAK inhibitor

JAK1 0 N/A JAK inhibitor

JAK3 0 N/A JAK inhibitor

 IL7R 0 N/A JAK inhibitor

SH2B3 0 N/A JAK inhibitor

Others Children- NTRK3 1 ETV6 TRK inhibitor

2.8%
FLT3 1 ZMYM2 FLT3 inhibitor

Adolescen FGFR1 1 BCR FGFR

t(16-21 inhibitor
yrs)-3% BLNK 1 DNTT Unknown

Young
adult(21-
39 yrs)-

of
5.2%

ro
Adult (40-
86 yrs)-
3.1% -p
re
lP
na
ur
Jo
 Table -4
Baseline characteristics of included studies
No References ALL PhLI Gender MEDIAN Media Ph like Specific gene detection Study Study type
KE (M/F) AGE OF n screening method period
(years, WBC METHOD
RANGE) COU USED
NT ×

f
109/L

o
1 Den Boer et 246 44 NR 6.5 36.5 HC RT-PCR for kinase 1990- Prospective

ro
al 2009 (2) method 2004

-p
2 Harvey et al 207 29 Male-21 14.2 92.7 PAM FISH, Flow cytometry, 2000 - Retrospective
Female- PCR 2003

re
2010 (6)
8

lP
3 Roberts et al 1157 158 NR NR NR PAM mRNA sequencing, 2000- Retrospective
2012 (13) WGS, RT- PCR, SNP 2010

na
array analysis
4 Maude et al 21 18 NR NR NR Xenograft Phosphoflow cytometry, NR Retrospective

5
2012 (16)
Loh et al. 572 81 NR NR
ur NR
models
PAM
Immunoblotting
FISH, RT-PCR 2000- Retrospective
Jo
2013 (7) 2010
6 Veer et al 1128 94 NR NR NR HC Multiplex ligation- 1994- Retrospective
2013 (14) dependent Probe 2015
amplification (MLPA)
7 Roberts et al 344 40 Male-27 5.3 (1.3- 7.1 PAM FISH, RT-PCR, RNA 2000- Prospective
2014 (3) Female- 18.6) (1.7- sequencing, Sanger 2007
13 258.3) sequencing (NGS),
Genomic PCR
8 Roberts et al 1725 264 NR NR NR PAM FISH, RT-PCR, RNA 2000- Retrospective
2014 (4) sequencing, Genome 2007
sequencing (NGS)
9 Boer et al 127 21 NR 25(16-59) NR HC RT-PCR 1993- Prospective
2015 (15) 2009
10 Andreu et al 308 44 NR NR NR PAM NR NR Retrospective
2015 (8)
11 Jain et al 148 49 NR NR NR PAM flow cytometry FISH NR Retrospective
2016 (9)
12 Iacobucci et 212 NR NR NR NR Sanger sequencing, NR Retrospective

o f
3115 whole genome
al 2016(31)

ro
sequencing
13 Konoplev et 126 10 NR NR NR Multiparamete Multiparameter flow 2013 - Prospective

-p
r flow cytometry (MFC), FISH 2015
al 2017 (19)

re
cytometry
14 Tasian et al 87 18 NR 28.6(19- 28.6 PAM FISH, RT-PCR NR Retrospective

lP
63)
2017 (10)

na
15 Herold et al 207 26 NR 31 (16-69) NR PAM FISH, RT-PCR, Copy 1999 - Retrospective
(B- number alterations were 2005
2017 (11)
ALL
) ur analyzed using the SALSA
multiplex
Jo
ligation-dependent probe
amplification kit P335-B1
16 Heatley SL 245 19 NR NR NR PAM FISH, NGS, SNP 2002- Retrospective
Microarray 2011
et al 2017
(12)
17 Roberts et al 798 194 Male - 40 (21-86) 56.6 PAM FISH NR Retrospective
119 (0.2- DNA copy number
2017 (5)
Female- 434) alterations SNP profiling
73 (range
)
18 Reshmi et al 1389 284 NR NR NR TaqMan LDA Reverse transcriptase 2010 - Retrospective
polymerase polymerase chain reaction, 2014
2017 (17)
chain reaction Transcriptome sequencing,
(PCR)assay FISH
19 Roberts et al 1023 139 NR <10 years <50 8-gene TaqMan PCR on the 2006 - Retrospective
TaqMan low- LDA card, FISH, 2008
2018 (39)
density Sanger sequencing,
array (LDA) RT-PCR,

f
polymerase Transcriptome sequencing

o
chain reaction analysis

ro
(PCR) assay

-p
re
lP
na
ur
Jo
 o f
ro
-p
re
lP
na
ur
Jo

Figure -1 Current Ph-like ALL genetic testing algorithm

 Articles identified from search of
PubMed (n=60) and Google
scholar (n=67) based on
keywords

Excluded due to
exclusion criteria (n=78)

Included for full length review

of
(n=50)

ro
Excluded based on non-
-p available baseline
characteristic parameters
re
(n=31)
lP

Included for baseline

characteristic analysis (n=19)
na
ur

Figure 2: Flow Diagram according to PRISMA Format

Jo