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2024-09-16T13:10:09.000Z

Ph-like ALL: An overview of the genomic landscape, epidemiology, diagnosis, and treatment


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Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL associated with poor clinical outcomes, including high rates of induction failure, minimal residual disease (MRD) persistence, and relapse. It is characterized by a similar gene expression profile to Philadelphia-positive ALL, but lacks the BCR-ABL1 fusion gene.1 Although Ph-like ALL can occur at any age, it most frequently occurs in adolescents and adults.2

In this article, we provide an overview of the epidemiology, clinical characteristics, genomic landscape, diagnosis, and treatment strategies of Ph-like ALL.

Epidemiology and clinical characteristics3,4

The epidemiology of Ph-like ALL is shown in Figure 1.

Compared with non-Ph-like ALL, patients with Ph-like ALL have2,3:

  • A higher leukocyte count (106,000 vs 59,000 per cubic millimeter; p < 0.001) at diagnosis
  • A significantly lower 5-year overall survival rate (23% vs 59%; p = 0.006)
  • Increased minimal residual disease levels after remission induction, lower continuous remission rates, and higher relapses
  • Increased risk of treatment failure/induction failure

Genomic landscape

Ph-like ALL is a genetically heterogenous disease involving a spectrum of genetic alterations, activating cytokine receptor genes and kinase-signaling pathways; these are categorized into four genomically-defined subsets based on the similarity of functional fusion partners and underlying kinase-activating lesions (Table 1):

  • JAK/STAT pathway gene alterations;
  • ABL class alterations;
  • Ras pathway mutations; and
  • rare kinase fusions.

Table 1. Genomic landscape of Ph-like ALL kinase rearrangements, therapeutic targets, and clinical trials*

3’ kinase gene 5’ fusion partner genes Kinase inhibitors Clinical trials
JAK/STAT pathway alterations
CRLF2 CSF2RA, IGH, P2RY8 Ruxolitinib NCT024207175 (terminated)
JAK2 ATF7IP, BCR, EBF1, ETV6, GOLGA5, HMBOX1, OFD1, PAX5, PCM1, PPFIBP1, RFX3, SMU1, SNX29, SSBP2, STRN3, TERF2, TPR, USP25, ZBTB46, ZNF274, ZNF340 Ruxolitinib NCT027239946
EPOR IGH, IGK, IGL, LAIR1, THADA Ruxolitinib NCT031177517
TSLP IQGAP2 Ruxolitinib
IL2RB MYH9 Ruxolitinib NCT035713218
ABL class alterations
ABL1 CENPC, ETV6, FOXP1, LSM14A, NUP153, NUP214, RANBP2, RCSD1, SFPQ, SHIP1, SNX1, SNX2, SPTNA1, ZMIZ1 Dasatinib, imatinib, others NCT028830499
ABL2 PAG1, RCSD1, ZC3HAV1 Dasatinib, imatinib NCT0214341410
CSF1R MEF2D, SSBP2, TBL1XR1 Dasatinib, imatinib NCT024207175

PDGFRA

FIP1L1 Dasatinib, imatinib NCT0300714711

PDGFRB


ATF7IP, EBF1, ETV6, NUMA1, SNX29, SSBP2, TERF2, TNIP1, ZEB2, ZMYND8, ZNF608 Dasatinib, imatinib NCT031177517
LYN GATAD2A, NCOR1 Dasatinib, imatinib
Other kinases
NTRK3 ETV6

Entrectinib

Larotrectinib

NCT0306666112

NCT0383496113
PTK2B KDM6A, STAG2, TMEM2 FAK inhibitors
FGFR1 BCR Ponatinib
FLT3 ZMYM2 FLT3 inhibitors
TYK2 MYB, SMARCA4, ZNF340 JAK1/3 inhibitor
BLNK DNTT
CBL KANK1
DGKH ZFAND3
ALL, acute lymphoblastic leukemia; FAK, focal adhesion kinase; JAK, Janus kinase; Ph-like, Philadelphia chromosome-like.
*Adapted from Tran and Tasian.1

Key genomic alterations in Ph-like ALL are summarized in Figure 3.

Diagnosis

Given the genetic heterogeneity of Ph-like ALL, clinical diagnosis remains challenging; there is currently no standardized approach.1,15 The diagnostic approach of Ph-like ALL relies on a combination of gene expression profiling, reverse transcription polymerase chain reaction, fluorescence in situ hybridization, immunophenotyping, and DNA sequencing. Performing clinical diagnostics has predictive and prognostic implications, facilitating better risk stratification and personalized treatment approaches for patients with Ph-like ALL.3

A practical, cost-effective, and time-efficient clinical algorithm to screen the Ph-like gene expression profile among all newly diagnosed patients with high-risk B-ALL was suggested by Harvey and Tasian 16 (Figure 4).

Management

To date, there is no standard treatment for patients with Ph-like ALL. Given the lack of guidelines, referral to clinical studies is recommended for newly diagnosed cases.17 If there are no studies available, the patients age and pre-existing comorbidities are considered when selecting appropriate therapies18

  • Young patients, aged <40 years, are generally treated with pediatric-inspired regimens, such as C10403 or a modified Berlin-Frankfurt-Munich protocol.
  • Given the poor outcomes with conventional chemotherapy in older patients, enrolment in frontline clinical studies, particularly those incorporating novel agents, is strongly encouraged.
  • If no studies are available, a modified adult-based regimen focused on reducing treatment related toxicities to allow the early introduction of salvage therapy with novel agents.
  • Across all ages, an earlier switch from chemotherapy to novel agents is recommended for poor responders or those with persistent MRD.

Tyrosine kinase inhibitors

Given that most cases of Ph-like ALL involve genetic alterations in kinases and/or cytokine receptors, the application of tyrosine kinase inhibitors (TKIs) has become an area of active research. In preclinical studies, TKIs have shown promising outcomes in patients with Ph-like ALL harboring either ABL-class fusions and JAK-STAT activating alterations. These encouraging results have led to a number of further clinical trials examining these novel agents in combination with established chemotherapy regimens.14,18

In addition, numerous single case reports exist detailing the benefits of the TKIs dasatinib and imatinib for patients with Ph-like ALL with ABL1 class fusions, either for slow responders, as salvage therapy for relapsed/refractory disease, or as preemptive maintenance therapy post-allogenic hematopoietic cell transplant in patients with persistent MRD.14,18 Among patients carrying the ABL-class fusion with a slow response on the UKALL2011 who were prospectively treated with imatinib, the 4-year relapse rate was 0% vs 62.5% and the event-free survival rate was 83.9% vs 37.5% for the TKI vs control groups, respectively.14

While several case reports have demonstrated clinical activity with ruxolitinib in combination with chemotherapy in JAK2-rearranged ALL, evidence for its single agent activity is largely unknown. The phase I part of the AALL1521 study (NCT02723994)6 demonstrated the efficacy and safety of ruxolitinib combined with chemotherapy in patients with B-cell ALL, harboring CRLF2, or JAK pathway alterations.18

Allogeneic stem cell transplantation

Allo-HSCT is a well-established for preventing relapse and is recommended as consolidation therapy for adults with high-risk ALL.19 An MRD-oriented approach, which was commenced in the GIMEMA LAL1913 study (NCT02067143)20, demonstrated that more patients with Ph-like ALL were allocated to transplant compared with patients with non-Ph-like ALL (53% vs 20%, respectively).18 Allo-HSCT is suggested for adults with Ph-like ALL who have persistent MRD post-consolidation, on an individual basis (considering age, chemotherapy resistance, and other risk factors).18

For older patients, transplant is considered as consolidation therapy based on donor availability, irrespective of MRD response.18 Although HSCT has shown promise in patients with Ph-positive ALL, its role in the treatment of Ph-like ALL is still unclear. El Fakih et al. suggested a treatment algorithm concerning when to consider Allo-HSCT in Ph-like ALL patients (Figure 5).20 Further studies are needed to fully elucidate the value of HSCT in this disease subset.19

Targeted immunotherapies14,18

Considering the chemotherapy-resistant nature of Ph-like ALL, novel targeted immunotherapies have been investigated, such as those already approved for the treatment of B-ALL. Blinatumomab, a bispecific CD3/CD19 antibody, is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of B-cell precursor ALL. In adult patients with relapsed/refractory ALL, blinatumomab has demonstrated encouraging response rates, with a complete response/complete response with incomplete count recovery of 75% and 57% in CRLF2r and non-CRLF2, respectively.14,18

Inotuzumab ozogamicin, a CD22 antibody drug-conjugate, has demonstrated a compositive complete response of 54% among 12 patients with Ph-like ALL and has yielded comparable response rates for Ph-like and non-Ph-like cohorts. The ongoing frontline studies evaluating the addition of blinatumomab (ECON-ACRIN E1910; NCT02003222)21 or inotuzumab ozogamicin (A041501 Alliance study; NCT03150693)22 to chemotherapy regimens in adults with newly diagnosed Ph-negative ALL could provide insights on its potential in Ph-like ALL.18  

CD19-targeted chimeric antigen receptors have demonstrated excellent response rates in both adults and children with advanced B-ALL. Although no study has investigated these novel therapies specifically in Ph-like ALL, it is likely that a significant proportion of the patients have Ph-like disease.18 Table 2 shows the current targeted therapies under investigation for Ph-like ALL.

Table 2. Key cellular targeted therapies for Ph-like ALL*

Therapy Key cellular targets Mechanism of action Phase of clinical trials
Birinapant TNF-α dependent SMAC mimetic In vitro and in vivo studies
CHZ868 JAK2 mutated Type 2 JAK2 inhibitor In vitro and in vivo studies
Dasatinib SRC/ABL class tyrosine kinase fusions Type 2 SRC/ABL class tyrosine kinase inhibitor Phase II and III clinical trials
Gedatolisib PI3K and mTOR Dual inhibitor of PI3K-α,
PI3K-
у, and mTOR
In vitro and in vivo studies
Givinostat CRLF2+ Class 1 and 2 HDAC inhibitor In vitro and in vivo studies
JQI CRLF2+ BET inhibitor In vitro and in vivo studies
Ponatinib SRC/ABL class tyrosine kinase fusions Type 3 SRC/ABL class tyrosine kinase inhibitor Single case study
Ruxolitinib JAK2-mutated Type I JAK2 inhibitor Phase II clinical trials
Rapamycin mTOR activated pathways mTOR inhibitor In vitro and in vivo studies
Luminespib CRLF2+ HSP90 inhibitor In vitro and in vivo studies
Selumetinib and AZD1480 CRLF2+ MEK 1/2 inhibitor and ATP-competitive JAK2 inhibitor In vitro studies
TSLPR CAR T cells CRLF2+ Allogeneic TSLPR CAR T cells In vitro and in vivo studies

CAR, chimeric antigen receptor; TSLPR, thymic stromal lymphopoietin receptor.
*Adapted from Kotb, et al.3

A summary of clinical trials on patients with newly diagnosed and R/R Ph-like ALL is shown in Table 3. 

NCT (status) Treatment Patient population Phase and group (number of patients)
NCT028830499
(ongoing)
Dasatinib Newly diagnosed high-risk B-ALL including Ph-like ALL
Age: 1−30 years
Phase III COG trial (N = 5,956)
NCT027239946
(ongoing)
Ruxolitinib, chemotherapy Children with de-novo high-risk CRLF2-rearranged and/or JAK pathway-mutant ALL
Age: 1
21 years
Phase II COG trial (N = 170)
NCT031177517
(ongoing)
Ruxolitinib, blinatumomab Newly diagnosed patients with B-ALL
Age: 1
18 years
Phase II/III SJCRH trial (N = 1,000)
NCT035713218
(ongoing)
Ruxolitinib Newly diagnosed Ph-like ALL
Age: 18−39.99 years
Phase I; University of Chicago
(N = 15)
NCT0364327623
(ongoing)
Bortezomib,
Blinatumomab,
Newly diagnosed ALL
Age: ≤17 years
Phase III; AIEOP/BFM
(N = 5,000)
NCT0300714711
(ongoing)
Imatinib Newly diagnosed ALL with ABL class fusion
Age:2−21 years
Phase III; COG/EsPhALL
(N = 475)
NCT0450161424
(active; not recruiting)
Ponatinib Resistant/refractory Ph + or Ph-like ALL
Age: ≥1−21 years
Phase I/II; COG
(N = 68)
NCT0383496113
(active; not recruiting)
Larotrectinib Relapsed acute leukemia with TRK fusion
Age: 0-≤30 years
Phase II; COG
(N = 70)
NCT03040030 Dasatinib De novo B-All with ABL class fusion
Age: ≥1−21 years
Phase III; DFCI
(N = 560)
NCT0391112825
(ongoing)
Imatinib Newly diagnosed ALL
Age: ≥1–45 years
Phase III; ALLtogether
(N = 500)
NCT0214341410 Dasatinib Newly diagnosed or relapsed Ph-like ALL
Age: ≥65 years
Phase II; SWOG
(N = 57)
NCT0327549326
(ongoing)
NCT0361485827
CART-19/22 Relapsed/refractory ALL
Age: 6−65 years
Phase I/II; Hospital of Soochow University
(N = 17)
NCT0318112628
(completed)
Venetoclax, navitoclax Relapsed/refractory ALL
Age: ≥4 years
Phase I; Pullarkat, et al.
(N = 69)
AIEOP, Associazione Italiana di Ematologia Oncologia Pediatrica; ALL, acute lymphoblastic leukemia; BFM, Berlin-Frankfurt-MünsteR; CAR-T, chimeric antigen receptor T-cell; COG, children’s oncology group; DFCI, Dana-Farber Cancer Institute; Ph, Philadelphia chromosome; SJCRH, St Jude Children’s Research Hospital; SWOG, Southwest Oncology Group.
*Data from Alghandour, et al.29
  1. Tran TH, Tasian SK. Has Ph-like ALL superseded Ph+ ALL as the least favorable subtype? Best Practice & Research Clinical Haematology. 2021;34(4):101331. DOI: 10.1016/j.beha.2021.101331
  2. Tran TH, Loh ML. Ph-like acute lymphoblastic leukemia. Hematology. 2016;2016(1):561-566. DOI: 10.1182/asheducation-2016.1.561
  3. Kotb A, El Fakih R, Hanbali A, et al. Philadelphia-like acute lymphoblastic leukemia: diagnostic dilemma and management perspectives. Experimental Hematology. 2018;67:1-9. DOI: 10.1016/j.exphem.2018.07.007
  4. Pui CH, Roberts KG, Yang JJ, et al. Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2017;17(8):464-470. DOI: 10.1016/j.clml.2017.03.299
  5. ClinicalTrials.gov. Ruxolitinib phosphate or dasatinib with chemotherapy in treating patients with relapsed or refractory Philadelphia chromosome-like acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT02420717. Updated May 08, 2024. Accessed Sep 03, 2024.
  6. ClinicalTrials.gov. A phase 2 study of ruxolitinib with chemotherapy in children with acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT02723994. Updated Jun 27, 2024. Accessed Sep 03, 2024.
  7. ClinicalTrials.gov. Total therapy XVII for newly diagnosed patients with acute lymphoblastic leukemia and lymphoma https://classic.clinicaltrials.gov/ct2/show/NCT03117751. Updated Mar 05, 2024. Accessed Sep 03, 2024.
  8. ClinicalTrials.gov. Ruxolitinib and chemotherapy in adolescents and young adults with Ph-like acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT03571321. Updated Nov 29, 2023. Accessed Sep 03, 2024.
  9. ClinicalTrials.gov. Combination chemotherapy in treating young patients with newly diagnosed high-risk B acute lymphoblastic leukemia and Ph-like TKI sensitive mutations https://classic.clinicaltrials.gov/ct2/show/NCT02883049. Updated Aug 21, 2024. Accessed Sep 03, 2024.
  10. ClinicalTrials.gov. Blinatumomab and combination chemotherapy or dasatinib, prednisone, and blinatumomab in treating older patients with acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT02143414. Updated Jul 24, 2024. Accessed Sep 03, 2024.
  11. ClinicalTrials.gov. Imatinib mesylate and combination chemotherapy in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT03007147. Updated Aug 15, 2024. Accessed Sep 03, 2024.
  12. ClinicalTrials.gov. Expanded access to entrectinib for cancers with NTRK1/2/3, ROS1, or ALK gene fusions https://classic.clinicaltrials.gov/ct2/show/NCT03066661. Updated Apr 26, 2019. Accessed Sep 03, 2024.
  13. ClinicalTrials.gov. Larotrectinib in treating patients with previously untreated TRK fusion solid tumors and TRK fusion relapsed acute leukemia https://classic.clinicaltrials.gov/ct2/show/NCT03834961. Updated Aug 15, 2024. Accessed Sep 03, 2024.
  14. Iacobucci I, Roberts KG. Genetic alterations and therapeutic targeting of Philadelphia-like acute lymphoblastic leukemia. Genes. 2021;12(5):687.
  15. Avraham F, Yishai O. How I diagnose and manage Philadelphia chromosome-like acute lymphoblastic leukemia. Haematologica. 2019;104(11):2135-2143. DOI: 10.3324/haematol.2018.207506
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  17. Prescott K, Jacobs M, Stock W, et al. New approaches to treating challenging subtypes of ALL in AYA patients. Current Hematologic Malignancy Reports. 2020;15(6):424-435. DOI: 10.1007/s11899-020-00597-y
  18. Aldoss I, Advani AS. Have any strategies in Ph-like ALL been shown to be effective? Best Practice & Research Clinical Haematology. 2021;34(1):101242. DOI: 10.1016/j.beha.2021.101242
  19. Vettenranta K, Dobsinska V, Kertész G, et al. What is the role of HSCT in Philadelphia-chromosome–positive and Philadelphia-chromosome–like ALL in the tyrosine kinase inhibitor era? Review. Frontiers in Pediatrics. 2022;9:1-10. DOI: 10.3389/fped.2021.807002
  20. ClinicalTrials.gov. MRD/​Risk-oriented therapy of adult Ph- ALL including pegylated asparaginase and lineage-targeted methotrexate (LAL1913) https://clinicaltrials.gov/study/NCT02067143. Updated Sep 08, 2021. Accessed Sep 03, 2024.
  21. ClinicalTrials.gov. Combination chemotherapy with or without blinatumomab in treating patients with newly diagnosed BCR-ABL-negative B lineage acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT02003222. Updated Dec 15, 2023. Accessed Sep 03, 2024.
  22. ClinicalTrials.gov. Inotuzumab ozogamicin and frontline chemotherapy in treating young adults with newly diagnosed B acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT03150693. Updated Aug 02, 2024. Accessed Sep 03, 2024.
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  24. ClinicalTrials.gov. A study of ponatinib with chemotherapy in children, teenagers, and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT04501614. Updated Aug 09, 2024. Accessed Sep 03, 2024.
  25. ClinicalTrials.gov. A treatment protocol for participants 0-45 years with acute lymphoblastic leukaemia https://classic.clinicaltrials.gov/ct2/show/NCT03911128. Updated Jul 12, 2024. Accessed Sep 03, 2024.
  26. ClinicalTrials.gov. Humanized CD19 CAR-T cells with CRS suppression technology for R/R CD19+ acute lymphoblastic leukemia https://classic.clinicaltrials.gov/ct2/show/NCT03275493. Updated May 28, 2024. Accessed Sep 03, 2024.
  27. ClinicalTrials.gov. CD19/​CD22-targeted chimeric antigen receptor engineered T Cell (CART) in B-cell acute lymphoblastic leukemia. https://clinicaltrials.gov/study/NCT03614858. Updated Nov 29, 2023. Accessed Sep 03, 2024.
  28. ClinicalTrials.gov. A study of venetoclax in combination with navitoclax and chemotherapy in subjects with relapsed/refractory acute lymphoblastic leukemia or relapsed/refractory lymphoblastic lymphoma https://classic.clinicaltrials.gov/ct2/show/NCT03181126. Updated Oct 14, 2021. Accessed Sep 03, 2024.
  29. Alghandour R, Sakr DH, Shaaban Y. Philadelphia-like acute lymphoblastic leukemia: the journey from molecular background to the role of bone marrow transplant—review article. Annals of Hematology. 2023;102(6):1287-1300. DOI: 10.1007/s00277-023-05241-2