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

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 characteristics^3,4

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

Compared with non-Ph-like ALL, patients with Ph-like ALL have^2,3:

• 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 immunotherapies^14,18

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

Key Guidelines and organizations

• ESMO clinical practice guidelines
• NCCN guidelines for physicians
• Cancer Research UK: treatment of acute lymphocytic leukemia.
• American Cancer Society: treatment of acute lymphocytic leukemia.
• Leukemia & Lymphoma Society: treatment of acute lymphocytic leukemia.
• NHS: treatment for acute lymphoblastic leukemia.
• NCCN guidelines for patients
• Patient empowerment network
• CancerCare
• Leukemia research foundation
• Know ALL