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Philadelphia-like acute lymphoblastic leukemia: diagnostic dilemma and management perspectives

Open AccessPublished:August 01, 2018DOI:https://doi.org/10.1016/j.exphem.2018.07.007

      Highlights

      • Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a new subgroup of ALL.
      • Ph-like ALL is characterized by high cytokine receptor and tyrosine kinase signaling.
      • Accurate and standard testing approaches are not widely available.
      • With the currently available therapies, the outcomes of Ph-like ALL are suboptimal.
      • Targeting the affected pathways might alter the prognosis of this new subgroup.
      Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by suboptimal outcomes in the adult age group. Recently, a new subtype called Philadelphia (Ph)-like ALL has been described. This subgroup is characterized by high cytokine receptor and tyrosine kinase signaling expression, resulting in kinase activation through stimulation of two main pathways, the ABL and JAK/STAT pathways. The diagnostic method or approach for Ph-like ALL is still not standardized and efforts are ongoing to identify an easy and applicable diagnostic method. Accurate and standard testing approaches are much needed and this will facilitate better understanding of this subgroup, including better estimation of the prevalence and incidence in different age groups and the clinical outcomes of such new entity. Here, we review the currently available diagnostic tools, activated pathways, and different therapeutic approaches used to target this subgroup.
      Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy treated with intensive chemotherapy [
      • Inaba H
      • Greaves M
      • Mullighan CG
      Acute lymphoblastic leukaemia.
      ]. In children, ALL therapy was a success story [
      • Hunger SP
      • Mullighan CG
      Acute lymphoblastic leukemia in children.
      ]; however, in adults, outcomes remain poor [
      • Goldstone AH
      • Richards SM
      • Lazarus HM
      • et al.
      In adults with standard—risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).
      ]. The poor prognosis of adult ALL is attributed to the accumulation of poor prognostic features, including, but not limited to, the higher frequency of poor-risk genomic subgroups, the lower tolerability to prolonged courses of intensive chemotherapy, and the high therapy-related mortality after hematopoietic cell transplantation (HCT) [
      • Gokbuget N
      How I treat older patients with ALL.
      ].
      A new category of poor-risk ALL, called Philadelphia (Ph)-like ALL, was recently identified [
      • Den Boer ML
      • van Slegtenhorst M
      • De Menezes RX
      • et al.
      A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
      ] and listed as a new provisional category in the World Health Organization 2016 classification [
      • Arber DA
      • Orazi A
      • Hasserjian R
      • et al.
      The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia.
      ]. This new group is defined by high expression of cytokine receptors and tyrosine kinase genes with a gene expression profile similar to that of Ph-positive ALL but without the characteristic BCR-ABL rearrangement [
      • Roberts KG
      • Morin RD
      • Zhang J
      • et al.
      Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.
      ]. Ph-like ALL seems to be common in the adult age group (>20%) and apparently carries a poor prognosis with currently available therapies [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ]. Within this Ph-like group, several subgroups have been distinguished depending on the altered kinases or cytokine receptors and these alterations will probably guide the choice of therapy to target the affected pathways in a personalized approach [
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ].

      Discovery and diagnosis of Ph-like ALL

      In 1999, acute myeloid leukemia (AML) and ALL were shown to have distinct gene expression profiles [
      • Lowenberg B
      • Downing JR
      • Burnett A
      Acute myeloid leukemia.
      ]. In 2002, different gene expression profiles in ALL were linked to certain cytogenetic abnormalities that have an impact on prognosis [
      • Yeoh EJ
      • Ross ME
      • Shurtleff SA
      • et al.
      Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.
      ,
      • Golub TR
      • Slonim DK
      • Tamayo P
      • et al.
      Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.
      ]. In 2009, two studies described a new subtype of B-cell ALL (B-ALL) characterized by poor outcomes and by mutations, rearrangements, and copy number alterations involving cytokine receptor or kinase genes other than the BCR-ABL fusion. The investigators from the Children's Oncology Group (COG) and St. Jude Children's Research Hospital (SJCRH) called this subgroup Ph-like ALL, whereas the Dutch group called it BCR-ABL1-like ALL [
      • Den Boer ML
      • van Slegtenhorst M
      • De Menezes RX
      • et al.
      A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
      ,
      • Tasian SK
      • Loh ML
      • Hunger SP
      Philadelphia chromosome-like acute lymphoblastic leukemia.
      ,
      • Mullighan CG
      • Su X
      • Zhang J
      • et al.
      Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
      ]. Later on the gene expression profile of this subgroup was shown to be similar to that of Ph-positive ALL [
      • Roberts KG
      • Morin RD
      • Zhang J
      • et al.
      Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.
      ].
      The COG/SJCRH group [
      • Mullighan CG
      • Su X
      • Zhang J
      • et al.
      Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
      ] defined the Ph-like signature based on the prediction analysis of microarrays classifier, which consists of 255 gene probe sets. Using this method, the investigators also showed frequent deletions of IKZF1 in this subgroup. However, the Dutch group [
      • Den Boer ML
      • van Slegtenhorst M
      • De Menezes RX
      • et al.
      A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
      ] used a method that relies on hierarchical clustering of 110 gene probes to classify pediatric ALL subtypes (high-hyperdiploidy, mixed-lineage leukemia [MLL]-rearranged, ETV6-RUNX1, TCF3, BCR-ABL, etc.). These two gene expression profiling (GEP) methods overlap by nine probe sets and this explains the different definition and incidence of Ph-like/BCR-ABL1-like ALL between the two groups [
      • Boer JM
      • Marchante JR
      • Evans WE
      • et al.
      BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures.
      ]. The majority of cases are concordant; however, some cases are discordantly defined as Ph-like by COG/SJCRH and BCR-ABL1-like by the Dutch group [
      • Boer JM
      • Koenders JE
      • van der Holt B
      • et al.
      Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL1-like subgroup characterized by high non-response and relapse rates.
      ].
      The diagnosis of Ph-like ALL is challenging, but it carries predictive and prognostic implications that help to better define the patient's risk and to personalize the treatment approach based on the presence of targetable mutations. GEP is cumbersome to use in daily clinical practice. Other methods relying on reverse transcription polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), or combination of immunophenotyping and DNA sequencing have been used [
      • Fasan A
      • Kern W
      • Nadarajah N
      • et al.
      Three steps to the diagnosis of adult Ph-like ALL.
      ,

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ]. Identifying sensitive and specific algorithms will be very helpful to identify and treat Ph-like ALL in daily clinical practice. Because Ph-like ALL is only found in patients with B-ALL lacking translocation of BCR-ABL, ETV6-RUNX1, TCF3- PBX1, or KMT2A (MLL), Herold et al. developed a flow chart to help in identifying Ph-like ALL based on these facts (Figure 1) [
      • Herold T
      • Gokbuget N
      Philadelphia-like acute lymphoblastic leukemia in adults.
      ]. Fasan et al. developed a different diagnostic algorithm based on: (1) analysis of cytokine receptor like factor 2 (CRLF2) expression; (2) FISH targeting ABL and Janus activated kinase (JAK) pathway activating fusions involving the genes ABL1, ABL2, CSF1R, PDGFRB, and JAK; and (3) fusion-specific RT-PCR for identification of the respective ABL and JAK fusion partner [
      • Fasan A
      • Kern W
      • Nadarajah N
      • et al.
      Three steps to the diagnosis of adult Ph-like ALL.
      ]. Another method used by St. Jude uses a 15-gene classifier that could be analyzed on low-density microarray cards [
      • Kang H
      • Roberts KG
      • Chen IML
      • et al.
      Development and validation of a highly sensitive and specific gene expression classifier to prospectively screen and identify B-precursor acute lymphoblastic leukemia (ALL) patients with a Philadelphia chromosome-like (Ph-like or BCR-ABL1-like) signature for therapeutic targeting and clinical intervention.
      ] and can identify Ph-like ALL with targetable mutations that may respond to tyrosine kinase therapy [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ]. Ideally, having a quick, user-friendly, sensitive, and specific diagnostic test or approach (e.g., PCR or FISH in Ph-positive ALL) will help to standardize the diagnostic approach. This will enable us to accurately identify these patients so that they can be enrolled in clinical trials to better define this group and to identify the best therapeutic approach. Eventually, as suggested by some investigators, ALL can be broadly divided into three categories with clearly defined prognosis and therapeutic modality: Ph-positive, Ph-like, and other B-ALL [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ].
      Fig 1
      Figure 1Algorithm for the identification of Ph-like ALL according to Herold et al. (19). PTK, protein tyrosine kinase; RNAseq, RNA sequencing; PCR, polymerase chain reaction; FISH, fluorescence in situ hybridization.

      Epidemiology

      The incidence of Ph-like ALL is variable depending on the ethnicity, age group, diagnostic method, and reference group (pre-B-ALL or whole ALL). In one study, 264 of 1725 pre-B-ALL cases (15.3%) among all age groups were labeled as Ph-like ALL [
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ]. This same study showed that the prevalence of Ph-like ALL increases with age (from 10% among children to 27% among young adults). In another report, Ph-like ALL accounted for 27.9% of young adults (age 21–39 years), 20.4% of adults (age 40–59 years), and 24.0% of older adults (age 60–86 years) [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ]. The M.D. Anderson Cancer Center group reported that 49/148 (33.1%) adult patients who underwent gene expression profiling of leukemic cells had Ph-like ALL [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ]. Conversely, a large European report showed that the incidence of Ph-like ALL was only 15% of pre-B-ALL cases [
      • Boer JM
      • Koenders JE
      • van der Holt B
      • et al.
      Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL1-like subgroup characterized by high non-response and relapse rates.
      ]. These differences are probably due to difference in the ethnicity of the patients and the diagnostic methods used by different groups. Briefly, the incidence of Ph-like ALL seems to be different depending on the age group (seems to be higher in young patients), ethnicity (seems to be higher in Hispanics), and diagnostic method used. Standardizing the diagnostic approach and definition will help us better estimate the incidence of Ph-like ALL.

      Genetic alteration and subtypes of Ph-like ALL

      ALL is a heterogeneous disease characterized by multiple structural variations, mutations, and chromosomal rearrangements that affect epigenetic regulation and cell growth and proliferation and eventually perturb normal lymphoid maturation [
      • Mullighan CG
      Genomic characterization of childhood acute lymphoblastic leukemia.
      ]. The widespread use of genome sequencing and profiling has shaped our understanding of the genetic basis of ALL and allowed researchers to identify recurring genetic abnormalities and, subsequently, to define new subtypes of ALL such as Ph-like ALL [
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ]. Based on the altered pathways, patients with Ph-like ALL are subdivided into three main groups: kinase alterations, cytokine receptor alterations, and other less frequent pathway activations such as the RAS pathway) [
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ,
      • Roberts KG
      • Mullighan CG
      Genomics in acute lymphoblastic leukaemia: insights and treatment implications.
      ].

      Kinase pathway alteration

      The majority of Ph-like ALL cases (90%) have activating kinase alterations [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ], particularly deletions of IKAROS Family Zinc Finger 1 (IKZF1), which are found in up to 80% of cases [

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ]. Normally, IKZF1 is involved in B-cell differentiation [
      • Heizmann B
      • Kastner P
      • Chan S
      Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals.
      ] and alterations of IKZF1 function portend a poor prognosis in pre-B-ALL [
      • Mullighan CG
      • Su X
      • Zhang J
      • et al.
      Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
      ]. The 5′ part of the fusion transcript leads to constitutive tyrosine kinase activation with no need for receptor stimulation or ligand binding; the 3′ part of the fusion transcript determines the cascade of downstream signal transduction and, potentially, which inhibitors could inhibit the activated cascade and therefore inhibit leukemic cell growth [
      • Herold T
      • Gokbuget N
      Philadelphia-like acute lymphoblastic leukemia in adults.
      ,
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ,
      • Boer JM
      • den Boer ML
      BCR-ABL1-like acute lymphoblastic leukaemia: from bench to bedside.
      ]. ABL gene rearrangements and fusions with different partner genes eventually leading to ABL kinase activation and leukemogenesis are also commonly identified in Ph-like ALL cases (9.8–12.6%). Other less common altered kinases include: platelet-derived growth factor receptor (PDGFR A and B), colony stimulating factor 1 receptor (CSF1R), fms-related tyrosine kinase 3 (FLT3), diacylglycerol kinase eta (DGKH), neurotrophic receptor tyrosine kinase 3 (NTRK3), protein tyrosine kinase 2 beta (PTK2B), and B-cell linker (BLNK) [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ,
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ].

      Cytokine receptor pathway alterations

      CRLF2 alteration is a frequent abnormality in adult Ph-like ALL (50–60%) and tends to occur in older patients presenting with higher white blood cell count compared with non-CRLF2-rearranged Ph-like ALL. Additionally, CRLF2 appears to cluster in Hispanic patients compared with other ethnicities (78% of patients with CRLF2 overexpression were Hispanic), with the majority of rearrangements involving IGH-CRLF2 (57.6–76%), followed by P2RY8-CRLF2 (17–21%) [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ]. Rearrangements or sequence mutations of CRLF2 were found exclusively in the Ph-like subgroup [

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ] and, because it is the most frequent genetic alteration in Ph-like ALL, investigators are now building diagnostic algorithms that include flow cytometric assessment of surface CRLF2 overexpression (thymic stromal lymphopoietin protein receptor, TSLPR), followed by genetic confirmation of specific CRLF2 rearrangements [
      • Tasian SK
      • Doral MY
      • Borowitz MJ
      • et al.
      Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia.
      ,
      • Tasian SK
      • Hurtz C
      • Wertheim GB
      • et al.
      High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) in older adults with B-ALL.
      ]. CRLF2-overexpressed cases frequently have coexistent JAK mutation (∼47% of patients) and, theoretically, these cases can be targeted by JAK inhibitors [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ,
      • Jain N
      • Roberts KG
      • Jabbour EJ
      • et al.
      High-risk subtype of Ph-like acute lymphoblastic leukemia (ALL) in adults: dismal outcomes of CRLF2+ ALL patients treated with intensive chemotherapy.
      ].

      Other pathway alterations

      Beyond kinase and cytokine receptor alterations, a significant number of Ph-like ALL patients have RAS pathway mutations (KRAS, NRAS, NF1, and BRAF) with downstream activation of the RAF-MEK-ERK kinase axis, a potential target for MEK inhibitors [
      • Suryani S
      • Bracken LS
      • Harvey RC
      • et al.
      Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia.
      ,
      • Wells J
      • Jain N
      • Konopleva M
      Philadelphia chromosome-like acute lymphoblastic leukemia: progress in a new cancer subtype.
      ,
      • Jerchel IS
      • Hoogkamer AQ
      • Aries IM
      • et al.
      RAS pathway mutations as predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia.
      ].
      In summary, using delicate genomic methods, the Ph-like ALL can be subdivided into different subgroups [
      • Tasian SK
      • Hurtz C
      • Wertheim GB
      • et al.
      High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) in older adults with B-ALL.
      ]. Currently, at least seven subgroups have been described depending on the altered pathway: (1) CRLF2 rearrangements (49.7%); (2) ABL fusions (ABL1, ABL2, CSF1R, and PDGFRB; 12.6%); (3) JAK2 (7.4%) or EPOR (3.9%) rearrangements; (4) genetic alterations of IL7R, FLT3, TYK2, SH2B3, IL2RB, JAK1, JAK3, and other JAK–STAT (12.6%); (5) Ras mutations (4.3%); (6) uncommon fusions (DGKH, NTRK3); and (7) others with no kinase-activating alterations (4.8%) [
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ]. Table 1 summarizes the frequently affected genes in Ph-like ALL [
      • Boer JM
      • den Boer ML
      BCR-ABL1-like acute lymphoblastic leukaemia: from bench to bedside.
      ].
      Table 1Fusion gene rearrangements in Philadelphia like ALL
      Inhibitor TypeFusion GeneProtein FunctionPartner Gene(S)Type of Fusion
      ABL classABL1Tyrosine kinaseETV6, NUP214, ZMIZ1, RCSD1, NUP153,SFPQ, RANBP2, SNX1, SNX2, SPTAN1, FOXP1Chimeric protein
      ABL2Tyrosine kinaseRCSD1,PAG1, ZC3HAV1Chimeric protein
      PDGFRBCytokine receptor tyrosine kinaseEBF1, ATF7IP, SSBP2, TNIP1, ZEB2, SNX29Chimeric protein
      CSF1RCytokine receptor tyrosine kinaseSSBP2, MEF2DChimeric protein
      PDGFRACytokine receptor tyrosine kinaseFIP1L1Chimeric protein
      JAK2 classJAK2Tyrosine kinasePAX5, BCR, ATF7IP, EBF1, PPFIBP1, SSBP2,STRN3, TPR, TERF2, ETV6, OFD1, SMU1, ZNF340Chimeric protein
      EPORCytokine receptorIGH, IGK, LAIR1, THADAOverexpression truncated protein
      CRLF2Cytokine receptorP2RY8, IGH, CSF2RAOverexpression
      MiscellaneousTYK2Tyrosine kinaseMYB, SMARCA4, ZNF340Chimeric protein
      NTRK3Cytokine receptor tyrosine kinaseETV6Chimeric protein
      FLT3Cytokine receptor tyrosine kinaseZMYM2Chimeric protein
      PTK2BTyrosine kinaseTMEM2Chimeric protein
      IL2RBCytokine receptorMYH9Overexpression

      Clinical characteristics and outcomes

      Clinical characteristics

      Ph-like ALL is more common in males, with a peak incidence among young adults. Furthermore, patients with Ph-like ALL generally have higher leukocyte counts at presentation compared with patients with non-Ph-like ALL (106,000 vs. 59,000 per cubic millimeter, p < 0.001) [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ,
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ]. Two adult studies have confirmed that the incidence of Ph-like ALL was higher (42%) in patients younger than 40 years of age compared with those 40 years or older (24%) (p = 0.02) [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ]. However, Herold et al. found no significant differences in baseline characteristics, including age, sex, white cell count, hemoglobin, and platelet count, between the Ph-like and remaining pre-B-ALL subgroups [

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ]. This can potentially be explained by differences in the comparative group between the studies and the differences of criteria used to define Ph-like ALL. Within the Ph-like ALL subgroups, the baseline characteristics seem to be different based on the altered pathway [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ]. Table 2 summarizes the clinical characteristics of Ph-like ALL.
      Table 2Ph-like ALL clinical characteristics
      VariableComments
      AgeMore common in adolescent and young adult
      EthnicityCommon in Hispanic
      GenderMale predominance
      Presenting WBCsHigher counts
      Molecular variationAssociated with IKZF1, CRLF2, JAK2, or ABL abnormalities
      Response and outcomeTend to have more induction failure and higher relapse rate
      PrognosisPoor
      Therapeutic approachTrials ongoing to add targeted therapy (targeting the altered pathway) to chemotherapy mirroring the Ph-positive ALL experience (ruxolitinib, TKI, etc.)

      Outcomes

      ALL is a chemosensitive disease and complete remission rates >90% are universally achieved in all subgroups, including Ph-like ALL; however, maintaining remission is less likely in Ph-like ALL. Increasing age is known to correlate with poor tolerance to chemotherapy and inferior outcomes in all subgroups of ALL and this holds true for Ph-like ALL as well [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ]. Several studies from different groups comparing adult and pediatric patients with Ph-like ALL with non-Ph-like ALL patients from the same age group showed lower continuous remission rates, higher relapses, and thus lower survival in the Ph-like group [
      • Den Boer ML
      • van Slegtenhorst M
      • De Menezes RX
      • et al.
      A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
      ,
      • Mullighan CG
      • Su X
      • Zhang J
      • et al.
      Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
      ,
      • Boer JM
      • Marchante JR
      • Evans WE
      • et al.
      BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures.
      ,

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ,
      • Jain N
      • Roberts KG
      • Jabbour EJ
      • et al.
      High-risk subtype of Ph-like acute lymphoblastic leukemia (ALL) in adults: dismal outcomes of CRLF2+ ALL patients treated with intensive chemotherapy.
      ,
      • Heatley SL
      • Sadras T
      • Nievergall E
      • et al.
      High prevalence of relapse in Australian children with Ph-like acute lymphoblastic leukemia despite risk adapted treatment.
      ,
      • Imamura T
      • Kiyokawa N
      • Kato M
      • et al.
      Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.
      ]. A study from M.D. Anderson Cancer Center showed that the 5-year overall survival (OS) for Ph-like ALL was significantly lower than that of the non-Ph-like ALL group (23% vs. 59%, p = 0.006), except for the MLL-rearranged group, who had a median OS of 10.2 months. This same study showed no difference in the complete remission rate and minimal residual disease (MRD) rate between the Ph-like CRLF2+ and the Ph-like non-CRLF2 group; however, the CRLF2-overexpressed subgroup had significantly inferior OS (5-year survival <20% in the CRLF2+ group), event-free survival, and remission duration compared with other genomic subgroups. Additionally, this study showed that, within the Ph-like group, the IKZF1 deletion did not affect OS, but the JAK2 mutation did affect survival significantly (median OS in JAK2-mutated patients was 18.8 months vs. 26.9 months for patients with wild-type JAK2, p = 0.012) [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ].
      The achievement of deep responses and MRD negativity also seem to be significantly less in the Ph-like subgroup, which translates to higher and earlier relapses after remission induction compared with other ALL subgroups [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ,

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ,
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ,
      • Loh ML
      • Zhang J
      • Harvey RC
      • et al.
      Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project.
      ]. MRD-guided therapy has been reported to mitigate the prognostic significance of Ph-like ALL in children; however, in adults, the Ph-like ALL outcomes remain poor despite the achievement of MRD negativity [
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ,
      • Roberts KG
      • Pei D
      • Campana D
      • et al.
      Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease.
      ]. In addition to age and MRD status, IKZF1 alteration, NRAS mutation, JAK2 mutation, and CRLF2 rearrangements also correlate with poor overall survival and outcomes [

      T Herold, S Schneider, K Metzeler, et al., Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica August 2016: haematol.2015.136366; https://doi:10.3324/haematol.2015.136366.

      ,
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ,
      • Harvey RC
      • Mullighan CG
      • Chen IM
      • et al.
      Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.
      ,
      • Dou H
      • Chen X
      • Huang Y
      • et al.
      Prognostic significance of P2RY8-CRLF2 and CRLF2 overexpression may vary across risk subgroups of childhood B-cell acute lymphoblastic leukemia.
      ].
      Overall, the outcomes of Ph-like ALL patients are inferior to the outcomes of non-Ph-like ALL patients (except for the MLL-rearranged subgroup), with consistently lower disease-free survival (DFS) and OS [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ,
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ,
      • Jain N
      • Roberts KG
      • Jabbour E
      • et al.
      Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
      ].

      Management and targeted therapies

      Advancements in genome-wide profiling have paved the way to a better and deeper understanding of Ph-like ALL genetic basics and recurrent alterations. These advancements helped investigators to use different pathway inhibitors to target these abnormally activated pathways in a personalized therapy approach. Two main pathways are frequently activated in Ph-like ALL cases, the JAK-STAT and ABL pathways, which makes these patients susceptible to tyrosine kinase inhibitors (TKIs) targeting these pathways [
      • Roberts KG
      • Morin RD
      • Zhang J
      • et al.
      Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.
      ,
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ]. Patients with CRLF2 rearrangements frequently (∼50%) have point mutations of JAK1 or JAK2, whereas patients with no CRLF2 rearrangements can have JAK2 fusion proteins, carry sequence mutations or copy number alterations activating JAK-STAT signaling (including IL7R, SH2B3, and JAK1) or truncating rearrangements of the erythropoietin receptor (EPOR) and all of these patients are considered JAK activated and are sensitive to ruxolitinib in vitro. Conversely, patients who harbor alterations or fusions involving the ABL-class genes (ABL1, ABL2, CSF1R, and PDGFRB) are sensitive to ABL1 TKIs [
      • Roberts KG
      • Gu Z
      • Payne-Turner D
      • et al.
      High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
      ,
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ,
      • Ofran Y
      • Izraeli S
      BCR-ABL (Ph)-like acute leukemia: pathogenesis, diagnosis and therapeutic options.
      ,
      • Iacobucci I
      • Li Y
      • Roberts KG
      • et al.
      Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia.
      ,
      • Schwab C
      • Ryan SL
      • Chilton L
      • et al.
      EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications.
      ,
      • Mullighan CG
      • Collins-Underwood JR
      • Phillips LAA
      • et al.
      Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia.
      ,
      • Russell LJ
      • Capasso M
      • Vater I
      • et al.
      Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia.
      ,
      • Hertzberg L
      • Vendramini E
      • Ganmore I
      • et al.
      Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.
      ,
      • Bercovich D
      • Ganmore I
      • Scott LM
      • et al.
      Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome.
      ,
      • Maude SL
      • Tasian SK
      • Vincent T
      • et al.
      Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.
      ,
      • Russell LJ
      • De Castro DG
      • Griffiths M
      • et al.
      A novel translocation, t(14;19)(q32;p13), involving [email protected] and the cytokine receptor for erythropoietin.
      ,
      • Weston BW
      • Hayden MA
      • Roberts KG
      • et al.
      Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia.
      ]. In addition, new fusion genes (GATAD2A-LYN fusion) are reported to activate SRC and are sensitive to dasatinib [
      • Yano M
      • Imamura T
      • Asai D
      • et al.
      Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion.
      ,
      • Tanaka H
      • Takeuchi M
      • Takeda Y
      • et al.
      Identification of a novel TEL-Lyn fusion gene in primary myelofibrosis.
      ]. FLT3-activating alterations are also reported in Ph-like ALL and these are sensitive to FLT3 inhibitors [
      • Annesley CE
      • Brown P
      The biology and targeting of FLT3 in pediatric leukemia.
      ,
      • Reshmi SC
      • Harvey RC
      • Roberts KG
      • et al.
      Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.
      ]. A small subgroup of Ph-like ALL patients have no targetable lesions [
      • Reshmi SC
      • Harvey RC
      • Roberts KG
      • et al.
      Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.
      ]. Imatinib, dasatinib (targeting ABL1, ABL2, CSF1R, and PDGFRB), and ruxolitinib (targeting JAK, CRLF2, and EPOR alterations) showed some activity in preclinical studies and case reports [
      • Reshmi SC
      • Harvey RC
      • Roberts KG
      • et al.
      Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.
      ,
      • Steeghs EMP
      • Jerchel IS
      • de Goffau-Nobel W
      • et al.
      JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia.
      ] and a number of phase II/III prospective clinical trials are recruiting patients to study the effect of ruxolitinib or dasatinib with chemotherapy in patients with Ph-like ALL (NCT02420717, NCT02723994, NCT02883049). Ruxolitinib works by freezing the JAK2 protein in its active, phosphorylated state and carries the risk of rebound activation when ruxolitinib is stopped. Type II JAK2 inhibitors, which inhibit JAK2 in its inactive, nonphosphorylated state, may possibly avoid this rebound effect, although this needs proof of concept [
      • Boer JM
      • den Boer ML
      BCR-ABL1-like acute lymphoblastic leukaemia: from bench to bedside.
      ,
      • Wu SC
      • Li LS
      • Kopp N
      • et al.
      Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia.
      ]. There are many new drugs in the preclinical setting for targeting Ph-like ALL pathways. Ruxolitinib and the mammalian target of rapamycin (mTOR) inhibitor rapamycin (sirolimus) were found to be effective against CRLF2 rearrangements with JAK2 mutations [
      • Maude SL
      • Tasian SK
      • Vincent T
      • et al.
      Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.
      ]. Treatment with the dual phosphoinositide 3-kinase/mTOR inhibitor gedatolisib in murine xenograft models resulted in near eradication of ALL in (CRLF2)/JAK-mutant models [
      • Tasian SK
      • Teachey DT
      • Li Y
      • et al.
      Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.
      ]. A recent study demonstrated that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome resistance to JAK inhibitor therapy in ALL cells [
      • Kucine N
      • Marubayashi S
      • Bhagwat N
      • et al.
      Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.
      ]. The histone deacetylase inhibitor givinostat exhibits potent antitumor activity against CRLF2-rearranged ALL by reducing STAT5 phosphorylation [
      • Savino AM
      • Sarno J
      • Trentin L
      • et al.
      The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.
      ]. In studies of other tumor models, cells expressing ETV6–NTRK3 responded to the ALK inhibitor crizotinib [
      • Roberts KG
      • Li Y
      • Payne-Turner D
      • et al.
      Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
      ,
      • Taipale M
      • Krykbaeva I
      • Whitesell L
      • et al.
      Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells.
      ]. Table 3 summarizes the medications under investigation to target the pathways of Ph-like ALL [
      • Wells J
      • Jain N
      • Konopleva M
      Philadelphia chromosome-like acute lymphoblastic leukemia: progress in a new cancer subtype.
      ].
      Table 3Targeted therapies under investigation for Ph-like ALL
      DrugPhase of Clinical Studies DevelopmentPh-Like ALL TargetMethod of Action
      Birinapant (TetraLogic)In vitro and in vivo studiesTNF-α dependentSMAC mimetic
      CHZ868 (Novartis)In vitro and in vivo studies (not for clinical use)JAK2 mutatedType 2 JAK2 inhibitor
      Dasatinib (Bristol-Myers Squibb)Phase 2 and 3 clinical trials in progressSRC/ABL class tyrosine kinase fusionsType 2 SRC/ABL class tyrosine kinase inhibitor
      Gedatolisib (Pfizer)In vitro and in vivo studiesPI3K and mTOR-activated pathwaysDual inhibitor of PI3K-α, PI3K-γ, and mTOR
      Givinostat (Italfarmaco)In vitro and in vivo studiesCRLF2+Class 1 and class 2 HDAC inhibitor
      JQ1 (Roche)In vitro and in vivo studiesCRLF2+BET inhibitor
      Ponatinib (Ariad)Single case studySRC/ABL class tyrosine kinase fusionsType 3 SRC/ABL class tyrosine kinase inhibitor
      Ruxolitinib (Incyte)Phase 2 clinical trials in progressJAK2-mutatedType I JAK2 inhibitor
      Rapamycin (Pfizer)In vitro and in vivo studiesmTOR-activated pathwaysInhibitor of mTOR
      Luminespib (Novartis)In vitro and in vivo studiesCRLF2+HSP90 inhibitor
      Selumetinib (Astra-Zeneca) and AZD1480 (InvivoGen)In vitro studiesCRLF2+MEK 1/2 inhibitor and ATP-competitive JAK2 inhibitor
      TSLPR CAR T cells (National Cancer Institute)In vitro and in vivo studiesCRLF2+Allogeneic TSLPR CAR T cells
      BET=bromodomain and extra-terminal; CAR=chimeric antigen receptor; HDAC=histone deacetylase; SMAC=second mitochondria-derived activator of caspases; TNF-α=tumor necrosis factor alpha; TSLPR=thymic stromal lymphopoietin receptor
      In Ph-positive ALL, combining targeted therapy along with chemotherapy led to higher and deeper remissions and eventually better DFS and OS compared with chemotherapy alone [
      • Malagola M
      • Papayannidis C
      • Baccarani M
      Tyrosine kinase inhibitors in Ph+ acute lymphoblastic leukaemia: facts and perspectives.
      ]. Combination therapy trials for Ph-like ALL are the next step and currently being designed. Standard chemotherapy will probably remain a very important component to eliminate the bulk of leukemic cells and to avoid the outgrowth of clones or subclones with alternative activated pathways [
      • Boer JM
      • den Boer ML
      BCR-ABL1-like acute lymphoblastic leukaemia: from bench to bedside.
      ], whereas targeted therapies will probably aid in getting deeper and more sustained remission and as a long-term, low-toxicity maintenance strategy. The guidelines of major organizations such as the American Society for Blood and Marrow Transplantation, the National Marrow Donor Program (http://marrow.org/Physicians/When_to_Transplant/Referral_Guidelines.aspx), and the European Blood and Marrow Transplant Group (https://test.ebmt.org/Contents/Resources/Library/EBMTESHhandbook/Documents/EBMT2008_Cap21.pdf) have no clear recommendations on the use of HCT in patients with Ph-like ALL in CR1. This is partly because this is a new, not well-defined entity and partly because there are no sizable trials addressing this subgroup of patients. However, all major trials addressing the role of allo-HCT in CR1 for ALL patients showed that allo-HCT is the strongest modality available to decrease the relapse rate [
      • Goldstone AH
      • Richards SM
      • Lazarus HM
      • et al.
      In adults with standard—risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).
      ,
      • Sebban C
      • Lepage E
      • Vernant JP
      • et al.
      Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia.
      ,
      • Thomas X
      • Boiron JM
      • Huguet F
      • et al.
      Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.
      ,
      • Hunault M
      • Harousseau JL
      • Delain M
      • et al.
      Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial.
      ,
      • Cornelissen JJ
      • van der Holt B
      • Verhoef GE
      • et al.
      Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no–donor comparison.
      ], so it is reasonable to recommend allo-HCT for Ph-like ALL patients in first complete remission because of the higher relapse rate associated with this subgroup. Obviously, MRD-directed therapy is another reasonable approach to help allocate the highest-risk patients with persistent MRD for allo-HCT.

      Molecular genetics perspectives and future directions

      Advances in molecular technologies over the past decades helped to characterize the genetic basis of several disorders. Starting with karyotype analysis, which enable scientists to rearrange chromosomes and detect copy number changes, followed by the technology of using the loss of heterozygosity analysis, technologies keep moving forward. Recently, DNA/RNA sequencing resolved many of the most mysterious genomic mutations, including small insertions/deletions, base substitutions, rearrangements, and copy number alterations [
      • Yeoh EJ
      • Ross ME
      • Shurtleff SA
      • et al.
      Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.
      ]. In molecular testing, the Sanger sequencing technique is one of the most widely used analysis platforms for mutation detection. The innovation of the gene expression profiling, along with next-generation sequencing (NGS), led to advanced molecular subtyping with a promising future in earlier diagnosis, accurate prognosis, identification of targeted therapies, and eventually disease prevention. Using NGS, a panel of multiple genes could be screened for mutations in a single quick analysis with a considerably low cost through the application of massive parallel sequencing technology [
      • Zentner D
      • Thompson TN
      • James PA
      • et al.
      The cardiac genetics clinic: a model for multidisciplinary genomic medicine.
      ]. Proteomics have focused on different clinical applications, including identifying candidate biomarkers for diagnosis and early detection of disease, studying the pathogenesis of diseases, increasing the understanding of the mechanism of drug action, and identifying novel drug targets, along with the assessment of safety and efficacy of therapeutic interventions [
      • Petricoin EF
      • Zoon KC
      • Kohn EC
      • Barrett JC
      • Liotta LA
      Clinical proteomics: translating benchside promise into bedside reality.
      ,
      • Petricoin EF
      • Liotta LA
      Clinical applications of proteomics.
      ,
      • Rosenblatt KP
      • Bryant-Greenwood P
      • Killian JK
      • et al.
      Serum proteomics in cancer diagnosis and management.
      ,
      • Ramachandran N
      • Srivastava S
      • LaBaer J
      Applications of protein microarrays for biomarker discovery.
      ]. With the availability of these techniques worldwide, including in developing countries, the different or slightly different genetic landscape of Ph-like ALL might surface given the high rate of consanguinity and different lifestyles in different parts of the world. Currently, scientists are able to use high-throughput technologies including genomics, transcriptomics, proteomics, and metabolomics to reveal several diseases’ enigmatic secrets including Ph-like ALL. Characterizing the molecular genetic basis of Ph-like ALL at diagnosis by NGS will facilitate rapid, accurate, and cost effective diagnosis, along with identification or predictive and prognostic tools, which will translate into better management of such patients. Table 4 summarizes the currently available diagnostic methods of Ph-like ALL.
      Table 4Comparing available diagnostic methods of Ph-like ALL
      MethodAdvantageLimitations
      FISHEasily availableLimited to the specific probes and algorithm to follow; may miss many subtypes
      Gene sequencingCan detect all mutations and fusion genesExpensive and time consuming; not commercial available
      Low-density microarray (LDA) cardsquick, user friendly, sensitive and specific diagnostic testIdentifies only targeted mutations; requires frozen tissue

      Conclusions

      Ph-like ALL is a distinct subtype of high-risk ALL with poor prognosis. It is characterized by tyrosine kinase and cytokine receptor signaling gene alterations that lead to kinase activation through activation of two main pathways, the ABL and JAK/STAT pathways. The development of sensitive, cost-effective, standardized, and widely and commercially available diagnostic approaches is much needed in order to better identify these patients and enroll them in the appropriate trials. The incidence and outcomes of this group are poorly understood, in part because this is a relatively new entity, but mainly due to the lack of a well-standardized diagnostic method. Accurately identifying these patients early on during the disease process and enrolling them in trials is of utmost importance to answer some of the many remaining unknowns about Ph-like ALL (e.g., sensitivity to targeted agents, intensity of therapy, importance of combination therapy, value of MRD, necessity for HCT) to optimize the outcomes of this subgroup.

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