Treatment of EPOR-rearranged acute lymphoblastic leukemia with ruxolitinib: case reports and review of the literature

Abstract

Acute lymphoblastic leukemia (ALL) with erythropoietin receptor (EPOR) gene rearrangement is rarely reported. These patients test negative for the Philadelphia chromosome but exhibit a gene expression profile similar to that of Philadelphia chromosome-positive acute lymphoblastic leukemia, leading to their designation as Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). EPOR-rearranged ALL exhibits aggressive clinical course and dismal prognosis with a short remission duration and high level of minimal residual disease (MRD). The addition of tyrosine kinase inhibitors or Janus kinases inhibitors to conventional chemotherapy is an effective treatment approach for patients with Ph-like ALL. Here, we present two pediatric cases of Ph-like ALL with EPOR rearrangement that were treated with ruxolitinib and provide a literature review to assess the effectiveness of this treatment.

Introduction

Philadelphia chromosome-like acute lymphoblastic leukemia is a high-risk subtype defined by genomic alterations that activate cytokine receptor and tyrosine kinase signal pathway. This subtype accounts for approximately 15% of pediatric B-ALL, with a higher frequency of over 25% among adolescents and young adults. Key clinical characteristics include an older age at diagnosis, elevated white blood cell counts, and an adverse prognosis [1, 2]. Ph-like ALL display considerable genetic heterogeneity, with rearrangement of the cytokine receptor-like factor 2 (CRLF2) gene being the most prevalent alteration, representing about 50% of cases. Additionally, ABL-class fusions other than BCR::ABL1 account for 13% of Ph-like ALL instances [3]. EPOR rearrangement is a relatively rare type, accounting for 5–7% of cases. RNA sequencing data from the Pediatric Cancer Genome Project indicate that EPOR rearrangement occurs exclusively in B-ALL patients [4, 5].

The EPOR gene encodes a type 1 cytokine receptor involved in kinase signaling, typically located on the surface of erythroid progenitor cells and essential for normal erythroid development; however, it is not expressed in normal B-progenitor cells. EPOR rearrangement disrupts erythropoietin receptor expression in B-progenitor cells, promoting leukemogenesis through the activation of Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) signaling pathway. This rarely recognized group may exhibit resistance to conventional chemotherapy and has a dismal prognosis, with a 5-year disease-free survival rate of 26.1%, which is even lower than that of patients with CRLF2-rearranged ALL (38.8%) [1]. The addition of JAK inhibitors to conventional chemotherapy is an option for EPOR-rearranged ALL [6, 7]. In this report, we present two pediatric cases of Ph-like ALL with EPOR rearrangement that were treated with ruxolitinib and review the literature to discuss the effectiveness of ruxolitinib as a treatment option.

Case report

We conducted a search of the database at West China Second University Hospital from January 2020 to January 2024 and identified two patients with ALL associated with translocation t (14;19) (q32; p13). Based on bone marrow morphology and immunophenotypic profile, both patients were diagnosed with B-cell acute lymphoblastic leukemia (L2). Fluorescence in situ hybridization confirmed that they were Philadelphia chromosome negative (Fig. 1), and EPOR::IgH rearrangement was detected through whole transcription sequencing. We utilized multiplex ligation-dependent probe amplification analysis (MLPA) to identify IKAROS family zinc finger 1 (IKZF1) gene deletion. The first patient demonstrated loss of heterozygosity in IKZF1 exons 2–7, and due to a significant reduction in mitotic chromosomes in the bone marrow sample, karyotyping results could not be obtained. The second patient experienced a deletion in IKZF1 exons 4–8 and her karyotype was 47,XX,+8/46,XX, t (14;19) (q32; p13). Both patients exhibited no signs of central nervous system involvement.

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Fig. 1

Fluorescence in situ hybridization (FISH) analysis for MLL arrangement, BCR::ABL1 fusion, ETV6::RUNX1 fusion, CRLF2 rearrangement, ABL1 rearrangement, ABL2 rearrangement, PDGFRB rearrangement, CSF1R rearrangement

Given that both patients were over 10 years old at the time of diagnosis, they were stratified into intermediate risk (IR) group. On the day of diagnosis, they began induction chemotherapy (prednisone, vincristine, daunorubicin, peg-asparaginase) based on the Chinese Children Cancer Group 2020 (CCCG-ALL-2020) protocol. On day 19 (calculated from the start of chemotherapy), the first patient was initially evaluated using a bone marrow smear, which revealed that blast cells accounted for 69.5%, with minimal residual disease (MRD) of 81.67% assessed by flow cytometry. Additionally, Sanger sequencing confirmed the positive status of the EPOR::IgH gene (Fig. 2). Due to induction failure, ruxolitinib (100mg/m²/day, 14-days-on/14-days-off/month) was added to the early intensive chemotherapy regimen (mercaptopurine, cyclophosphamide, cytosine). She was reassessed by bone marrow smear on day 46, which showed complete remission (CR) with MRD of less than 0.01% and tested negative for EPOR::IgH. She subsequently received four cycles of consolidation chemotherapy (mercaptopurine and high-dose methotrexate) along with re-induction chemotherapy. Ruxolitinib was included at a dose of 100mg/m²/day (14-days-on/14-days-off/month) in each course of chemotherapy, and she maintained continuous complete remission (CCR). Nonetheless, during regular monitoring with bone marrow smears, the patient exhibited early relapse at the 20th month after diagnosis, registering MRD of 24.56% and testing positive for EPOR::IgH. Consequently, she was treated with chimeric antigen receptor T-cell therapy as salvage therapy regimen. On day 14 (from the initiation of CAR-T cell therapy), she attained CR once again, with MRD below 0.01% and a negative EPOR::IgH status. Following this, she underwent haploidentical sibling donor allogeneic hematopoietic stem cell transplantation (HSCT) and is currently in CR.

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Fig. 2

Lane 9 displays the PCR product for EPOR::IgH in Patient 1, featuring a distinct product band. A peak diagram illustrate the sequencing of the EPOR::IgH fusion product

The second patient responded well to induction chemotherapy, achieving MRD of less than 0.01% and testing negative for EPOR::IgH on day 19 and 46. To prolong her remission duration and improve survival, ruxolitinib (100mg/m²/day, 14-days-on/14-days-off/month) was added to her consolidation chemotherapy at the same dosage as the first patient. However, unlike the first patient, she experienced persistent and severe oral mucositis during the concurrent administration of mercaptopurine, high-dose methotrexate and ruxolitinib. We enhanced oral care and reduced the methotrexate dose to prevent further complications, resulting in a gradual subsiding of the oral mucositis. She maintained CCR until the maintenance chemotherapy phase. At 12 months post-diagnosis, she complained vomiting, headache and blurred vision in her left eye. While visual impairment, neurological examinations revealed no other positive findings. Bone marrow smear results, MRD status, EPOR::IgH fusion gene analysis, cerebrospinal fluid test, and visual evoked potentials were all normal. But eye magnetic resonance imaging highly suggestive of left retinal involvement (Fig. 3) and eventually we found leukemia cells in aqueous humor. Then, she underwent CAR-T and HLA-matched unrelated donor allogenic HSCT and she is currently in CR.

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Fig. 3

Eye magnetic resonance imaging suggested left retinal involvement

Discussion

Ph-like ALL is a subset of ALL characterized by the absence of the BCR::ABL1 fusion gene, yet its gene expression profile resembles that of Philadelphia chromosome-positive acute lymphoblastic leukemia [8]. EPOR rearrangement is a rare subtype that represents approximately 5–7% of Ph-like B-ALL and was first identified by Russell [9, 10, 11–12]. The morphologic and immunophenotypic features are not sufficiently distinctive to distinguish this subtype from other types of ALL [3]. In this study, we describe the clinical features of fourteen patients from our institution and the literature [13, 14, 15–16]. There are five males and nine females, with a median age of 22 years (Table 1). The peripheral blood specimens are hypercellular, with a median blast cell proportion of 54% (range 20–96%). Patients with EPOR rearrangement tend to be older and exhibit a higher blast cell count in peripheral blood at diagnosis. Immunophenotypic analysis conducted by flow cytometry reveals a stable, precursor B-cell immunophenotype. The above clinical manifestations align well with literatures, and no clinical, morphologic, or immunophenotypic characteristics can reliably predict EPOR rearrangement.

Table 1. Clinical features and treatments of fourteen EPOR rearrangement patients

No.	Age	Gender	Blasts in peripheral blood (%)	Karyotype	Molecular biology	Comorbidities/Complications	Treatments	EOI MRD	Outcomes
1 [13]	11	Male	68%	46, XY, t (14;19) (q32: p13.1)	EPOR::IgH	Erythrocytosis	1. Hyper-CVAD/MA regimen chemotherapy 2. Matched-sibling donor allogeneic HSCT	NM	Relapse after HSCT
2 [14]	40	Female	31%	46, XX, add (10) (q26), t (14;19) (q32; p13)	EPOR::IgH	No	1. VDCLP/MA regimen chemotherapy	NM	Died from relapse
3 [14]	23	Male	47%	46, XY	EPOR rearrangement	Aplastic anemia	1. IVP regimen chemotherapy 2. Ruxolitinib (Dose is unknown)	15.1%	MRD-negative leukemia remission
4 [15]	18	Female	62%	46, XX, t (14;19)	EPOR::IgH	CNS2b	1. Induction chemotherapy with vincristine, daunorubicin, L-asparaginase, and prednisone 2. Ruxolitinib (20mg/m2 twice-daily 14-days-on/14-days-off/month) 3. CAR T-cell therapy 4. Matched-sibling donor allogeneic HSCT	48%	MRD-negative leukemia remission
5 [15]	13	Female	69%	46, XX/56, XX with + X, + 2, +5, + 6, +8, + 9, +10, + 19, +21, + 22	EPOR::IgH	No	1. Induction chemotherapy with vincristine, daunorubicin, L-asparaginase, and prednisone 2. Ruxolitinib (50 mg/m2 twice-daily for 14-days-on/14-days-off/month)	5.7%	MRD-negative leukemia remission
6 [15]	17	Female	82%	46, XX	EPOR::IgH	No	1. Induction chemotherapy with vincristine, daunorubicin, L-asparaginase, and prednisone 2. Ponatinib 3. Consolidation therapy with cyclophosphamide, cytarabine, 6-mercaptopurine, and ponatinib 4. One cycle of blinatumomab with continued ponatinib 5. Matched-sibling donor (MSD) allogeneic HSCT	15%	MRD-negative leukemia remission
7 [16]	41	Female	20%	46, XX, t (14;19) (q32, p13.1)/46, XX	EPOR::IgH	No	1. Hyper-CVAD regimen chemotherapy 2. Ruxolitinib (Dose is unknown) 3. HSCT	NM	MRD-negative leukemia remission but died from sepsis
8 [16]	38	Female	25%	46, XX, t (14;19) (q32, p13.1)/46, XX	EPOR::IgH	No	1. BFM regimen chemotherapy 2. HSCT	NM	Died from graft vs. host disease
9 [16]	48	Female	96%	39 ~ 47, XX, del (6) (q23), add (5) (q35), + 8, add (8) (p23), + 11, t (14;19) (q32; p13.1), −18, −19, + 1 ~ 4mar[cp14]/46, XX	EPOR::IgH	No	1. Hyper-CVAD regimen chemotherapy 2. Blinatumomab	NM	Died from sepsis after relapse
10 [16]	74	Male	6%	44 ~ 45, XY, −4, del (6) (q21), t (14;19) (q32; p13.1), del (17) (p11.2) [cp10]/46, XY	EPOR::IgH	No	1. Hyper-CVAD regimen chemotherapy 2. Ruxolitinib (Dose is unknown) 3. Blinatumomab	NM	Died from pneumonia and sepsis after recurrence
11 [16]	21	Male	89%	46, XY, t (14;19) (q32, p13.1)	EPOR::IgH	No	1. Hyper-CVAD regimen chemotherapy 2. Re-induction chemotherapy with augmented BFM regimen chemotherapy after recurrence	NM	Died from sepsis after secondary recurrence
12 [16]	28	Male	59%	46, XY, t (14;19) (q32; p13.1)/46, XY	EPOR::IgH	No	1. Hyper-CVAD regimen chemotherapy 2. Blinatumomab	NM	Alive with disease after recurrence
13	14	Female	42%	47, XX, + 8/46, XX	EPOR::IgH	No	1. CCCG-ALL-2020 protocol chemotherapy 2. Ruxolitinib (100 mg/m2/day, 14-days-on/14-days-off/month)	< 0.01%	MRD-negative leukemia remission
14	14	Female	60%	Not detected	EPOR::IgH	No	1. CCCG-ALL-2020 protocol chemotherapy 2. Ruxolitinib (100 mg/m2/day, 14-days-on/14-days-off/month) 3. CAR T-cell therapy 4. Matched-sibling donor allogeneic HSCT	81.67%	Alive with disease after recurrence

Hyper-CVAD/MA regimen: cyclophosphamide, vincristine, doxorubicin, dexamethasone/high-dose methotrexate (MTX) and cytarabine

VDCLP/MA regimen: vindesine, cyclophosphamide, L-asparaginase, dexamethasone/ high-dose methotrexate (MTX) and cytarabine

IVP regimen: idarubicin, vindesine, prednisone

BFM regime: vincristine, prednisone, L-asparaginase, daunomycin, cytarabine, and methotrexate

EOI: end of induction chemotherapy

HSCT: hematopoietic stem cell transplantation

CAR T-cell therapy: chimeric antigen receptor T-cell therapy

NM: not mentioned

EPOR rearrangement is a poor prognostic marker and may indicate an impending relapse. Early detection and diagnosis are indeed of great importance. Philadelphia chromosome-positive acute lymphoblastic leukemia is typically screened using fluorescence in situ hybridization (FISH), but EPOR rearrangement may not be detected by conventional cytogenetic analysis due to its cryptic nature. Whole transcription sequencing, which is a more comprehensive tool for genetic analysis, can more sensitively identify these rare rearrangement [4, 17, 18].

Insufficient response to induction chemotherapy, high levels of MRD, and inferior EFS and OS are characteristics of Ph-like rearrangement. The 5-year EFS rate for Ph-like ALL is less than 60% in children and approximately 20% in adults [8, 19, 20]. Intensive chemotherapy and advanced molecular targeted therapies have been explored to improve prognosis, and JAK inhibitor compounds are being rapidly integrated into clinical practice [21, 22–23]. We present a list of currently terminated and ongoing clinical trials for pediatric and adolescent patients with Ph-like ALL (Table 2), which includs three clinical trials focused on the application of ruxolitinib.

Table 2. Clinical trials for pediatric and adolescents with Ph-like ALL

Genetic subgroups	Trials name/phase	objectives	Status
JAK-STAT pathway alterations	AALL1521/phase II (NCT02723994)	The study optimizes the dose of ruxolitinib in combination with the chemotherapy regimen and evaluates the efficacy of combination chemotherapy and ruxolitinib	Active/ not recruiting
	2014 − 0521/phase I/II (NCT02420717)	The trial studies the side effects and best dose of ruxolitinib phosphate and how well it works compared to dasatinib when given with chemotherapy in treating patients with relapsed/refractory Ph-like ALL	Terminated early (Due to low accrual and lack of response)
	Total Therapy XVII/phase II/III (NCT03117751)	The study determines the tolerability of combination therapy with ruxolitinib and early intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib	Active/ not recruiting
ABL-class alterations	ALL1631/phase III (NCT03007147)	Testing imatinib mesylate and combination chemotherapy in treating patients with newly diagnosed Ph + or Ph-like B-ALL	Active/ not recruiting
	ALL2131/phase III (NCT06124157)	Testing the combination of dasatinib or imatinib to chemotherapy treatment with blinatumomab for children, adolescents, and young adults with Ph + or Ph-like B-ALL	Recruiting
	ALL1131/phase III (NCT02883049)	Combination chemotherapy in treating young patients with newly diagnosed high-risk B-ALL and Ph-like TKI sensitive mutations	Active/ not recruiting
	AALL1922/phase I/II (NCT04501614)	The main aims of this study are to confirm the highest dose of ponatinib tablets and minitablet capsules that can be given to patients with Ph + or Ph-like B-ALL with acceptable side effects, and to evaluate if participant’s leukemia achieves remission	Terminated (Due to dose-limiting toxicities)
Other alterations	ADVL1823/phase II (NCT03834961)	This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back	Active/ not recruiting

In 2011, ruxolitinib, a JAK1 and JAK2 inhibitor, became the first JAK inhibitor approved for use in myelofibrosis by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) [24]. Subsequently, human leukemic cells with EPOR rearrangement have been shown to be sensitive to ruxolitinib in vitro [1, 4, 17]. In a systematic review, six pediatric patients with Ph-like ALL who received ruxolitinib after induction failure all achieved complete remission [25]. In our review, a total of fourteen patients with EPOR rearrangement received aggressive multi-agent chemotherapy as part of their initial treatment. Five of these patients had high end-induction MRD, while one patient had MRD of less than 0.01%, and eight patients lacked relevant data. Ruxolitinib was added to the chemotherapy regimen for 7 out of the 14 patients, and six of these patients achieved MRD negativity leukemia remission. Three patients subsequently underwent stem cell transplantation, while one received blinatumomab. Among the seven patients who did not receive ruxolitinib, one received one cycle of blinatumomab along with continued ponatinib and achieved negative MRD prior to hematopoietic stem cell transplantation. One other patient received blinatumomab and achieved remission after recurrence, but the remaining five patients sadly succumbed to relapse or complications. The improved survival rate underscored the viability of adding ruxolitinib to the treatment regimen for EPOR rearrangement [26, 27, 28–29].

Nonetheless, a phase I/II study of combining ruxolitinib or dasatinib with chemotherapy in patients with Ph-like ALL (NCT02420717) was prematurely terminated due to lack of efficacy. This trial focused on CRLF2-rearranged Ph-like ALL in patients aged 10 or above. Although the CRLF2-, JAK2-, and EPOR-rearranged subtypes of ALL are universally associated with constitutive activation of JAK/STAT signaling [30], half of CRLF2-rearranged ALLs have concomitant alterations in JAK pathway-associated genes, including JAK1 and JAK2, while a small number also harbor interleukin-7 receptor alpha (IL7α) gene mutations [31]. The EPOR gene encodes erythropoietin receptor, which is a member of cytokine receptor family. Upon bind to erythropoietin, this receptor activates JAK2 tyrosine kinase, which in turn initiates several intracellular pathways, including Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors (Fig. 4). EPOR rearrangement disrupts erythropoietin receptor expression in B-progenitor cells and leads to leukemogenesis through enhanced JAK2-STAT signaling [32, 33]. The pathway difference may explain why ruxolitinib exhibits exquisite sensitivity in the JAK2-rearranged and EPOR-rearranged subtypes.

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Fig. 4

Simplified overview of JAK–STAT signaling in EPOR-rearranged ALL

In our study, these patients initiated ruxolitinib treatment during different phases, exhibiting varying levels of tolerance and responses. This confirmed the potential of ruxolitinib but also highlighted some existing issues. First, the timing of ruxolitinib administration: although reports on pediatric patients with Ph-like ALL indicate that ruxolitinib is typically added to post-induction chemotherapy following first-line treatment failure or in case of relapse, we assume that using it after detecting EPOR rearrangement may be a reasonable approach. Second, rational therapeutic dose: a starting dose of 15 mg twice daily, with individualized dose escalation, was determined to be the most effective and safest regimen for ruxolitinib. A phase I dosing study (ADVL1011, NCT01164163) of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms recommended a continuous oral administration dose of 50 mg/m2 twice daily [29]. In other hematological diseases, the reported dosage of ruxolitinib can reach up to 200 mg twice daily, and the tolerance remains acceptable [34, 35–36]. In our center, ruxolitinib is given at a dose of 100 mg/m²/day according to the CCCG-ALL-2020 protocol, and we have not observed any severe cytopenia. Based on our study results and previous reports, it may be inferred that escalating the dose of ruxolitinib can lead to better resolution of Ph-like ALL with tolerable toxicity. A non-randomized clinical trial (AALL1521/INCB18424-269, NCT02723994) is currently investigating ruxolitinib dose in combination with a standard multi-agent chemotherapy regimen for the treatment of B-cell acute lymphoblastic leukemia. This trial is ongoing, and its results hold promise for future consideration. Third, adverse drug reactions and complications: the mechanism of action of ruxolitinib as a JAK1/JAK2 inhibitor theoretically predicts that thrombocytopenia and anemia would be common among most patients treated with ruxolitinib [37, 38]. However, in practice, pneumonia has been reported as the most frequently observed adverse event after 48 months of treatment [39]. In our center, no hematologic toxicity and severe infection were observed, but one patient suffered persistent and severe oral mucositis during concurrent treatment with methotrexate. This suggests that ruxolitinib may have a synergistic effect with certain medications, potentially exacerbating adverse drug reactions. Finally, while these findings and similar data support ruxolitinib as an effective long-term treatment option for patients with EPOR rearrangements, the most challenging task lies in implementing individually ruxolitinib therapy for Ph-like ALL. It is crucial to carefully assess and monitor each patient’s condition [40, 41, 42, 43–44].

Conclusion

The EPOR rearrangement B-ALL is a relatively rare subtype of Ph-like ALL and may go undetected by conventional cytogenetic analysis. An accurate initial molecular diagnosis, along with the integration of various treatment modalities, can offer the potential for improved response or even remission in patients with EPOR rearrangement B-ALL. Further studies of ruxolitinib in patients with Ph-like ALL are necessary to establish the clinical utility of this promising drug.

Acknowledgements

The authors would like to thank the patients and their parents.

Author contributions

Mingyan Jiang and Ju Gao: developed the study concept and revised the manuscript. Yiling Dai: analyzed and interpreted the data. Mingyan Jiang, Shuwen Sun and Yuan Ai: performed clinical treatment, cared for patients. Yiling Dai, Maoting Tang, Jinrong Li: collected the data and developed the figures. Yiling Dai: drafted the manuscript. All authors contributed to edit the manuscript and approved the submitted version.

Funding

This work was supported by the Sichuan Medical Association (No. S23008).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

This study was approved by the Ethics Committee of West China Second Hospital of Sichuan University. Written informed consent to participate in this study was provided by the participants’ legal guardians.

Consent for publication

Written informed consent for publication was obtained from the patients’ legal guardians.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Roberts, KG; Li, Y; Payne-Turner, D et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med; 2014; 371, 11 pp. 1005-1015.1:CAS:528:DC%2BC2cXhs1Olt73K [DOI: https://dx.doi.org/10.1056/NEJMoa1403088] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25207766][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191900]

2. Imamura, T; Kiyokawa, N; Kato, M et al. Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan. Blood Cancer J May; 2016; 13, 5 e419. [DOI: https://dx.doi.org/10.1038/bcj.2016.28]

3. Liu, W; Thakral, B; Tang, G; Wang, W; Medeiros, LJ; Konoplev, S. From the archives of MD Anderson cancer center: BCR-ABL1-like B acute lymphoblastic leukemia with IGH/EPOR fusion. Ann Diagn Pathol; 2020; 46, [DOI: https://dx.doi.org/10.1016/j.anndiagpath.2020.151514] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32330662]151514.

4. Iacobucci, I; Li, Y; Roberts, KG et al. Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia. Cancer Cell Feb; 2016; 8, 2 pp. 186-200.1:CAS:528:DC%2BC28XitlShu7o%3D [DOI: https://dx.doi.org/10.1016/j.ccell.2015.12.013]

5. Rusch, M; Nakitandwe, J; Shurtleff, S et al. Clinical cancer genomic profiling by three-platform sequencing of whole genome, whole exome and transcriptome. Nat Commun; 2018; 9, 11:CAS:528:DC%2BC1cXhvVSqsbzP [DOI: https://dx.doi.org/10.1038/s41467-018-06485-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30262806][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160438]3962.

6. 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. J Clin Oncol; 2013; 31, 25 pp. e413-416. [DOI: https://dx.doi.org/10.1200/jco.2012.47.6770] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23835704]

7. Lengline, E; Beldjord, K; Dombret, H; Soulier, J; Boissel, N; Clappier, E. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica Nov; 2013; 98, 11 pp. e146-e148. [DOI: https://dx.doi.org/10.3324/haematol.2013.095372]

8. 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. Lancet Oncol; 2009; 10, 2 pp. 125-134.1:CAS:528:DC%2BD1MXhtlGlurY%3D [DOI: https://dx.doi.org/10.1016/S1470-2045(08)70339-5]

9. Jain, S; Abraham, A. BCR-ABL1-like B-acute lymphoblastic leukemia/lymphoma: a comprehensive review. Arch Pathol Lab Med; 2020; 144, 2 pp. 150-155.1:CAS:528:DC%2BB3cXhtlSqtLvF [DOI: https://dx.doi.org/10.5858/arpa.2019-0194-RA] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31644323]

10. Khan, M; Siddiqi, R; Tran, TH. Philadelphia chromosome-like acute lymphoblastic leukemia: a review of the genetic basis, clinical features, and therapeutic options. Semin Hematol; 2018; 55, 4 pp. 235-241. [DOI: https://dx.doi.org/10.1053/j.seminhematol.2018.05.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30502852]

11. Russell, LJ; De Castro, DG; Griffiths, M et al. A novel translocation, t(14;19)(q32;p13), involving IGH@ and the cytokine receptor for erythropoietin. Leukemia; 2009; 23, 3 pp. 614-617.1:CAS:528:DC%2BD1MXivVKgsro%3D [DOI: https://dx.doi.org/10.1038/leu.2008.250] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18818706]

12. Roberts, KG; Morin, RD; Zhang, J et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell; 2012; 14, Aug pp. 153-166.1:CAS:528:DC%2BC38XhtF2ns7zK [DOI: https://dx.doi.org/10.1016/j.ccr.2012.06.005]

13. Sakamoto, K; Tanaka, S; Tomoyasu, C et al. Development of acute lymphoblastic leukemia with IgH-EPOR in a patient with secondary erythrocytosis. Int J Hematol; 2016; 104, 6 pp. 741-743. [DOI: https://dx.doi.org/10.1007/s12185-016-2083-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27544511]

14. Yang, Q; Shao, HG; Liu, HF et al. [Ph-like acute lymphocytic leukemia with EPOR rearrangement: 2 cases report and literatures review]. Zhonghua Xue Ye Xue Za Zhi Sep; 2018; 14, 9 pp. 773-775. [DOI: https://dx.doi.org/10.3760/cma.j.issn.0253-2727.2018.09.014]

15. Niswander, LM; Loftus, JP; Lainey, É et al. Therapeutic potential of ruxolitinib and ponatinib in patients with EPOR-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia. Haematologica; 2021; 106, 10 pp. 2763-2767. [DOI: https://dx.doi.org/10.3324/haematol.2021.278697] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34196168][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485673]

16. Jaso, JM; Yin, CC; Lu, VW et al. B acute lymphoblastic leukemia with t(14;19)(q32;p13.1) involving IGH/EPOR: a clinically aggressive subset of disease. Mod Pathol; 2014; 27, 3 pp. 382-389.1:CAS:528:DC%2BC3sXhsVOntbzP [DOI: https://dx.doi.org/10.1038/modpathol.2013.149] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24030742]

17. 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. Blood; 2017; 129, 25 pp. 3352-3361.1:CAS:528:DC%2BC2sXhsVOmsrzK [DOI: https://dx.doi.org/10.1182/blood-2016-12-758979] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28408464][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482101]

18. Tasian, SK; Loh, ML; Hunger, SP. Philadelphia chromosome-like acute lymphoblastic leukemia. Blood; 2017; 130, 19 pp. 2064-2072.1:CAS:528:DC%2BC1cXhs1ertbfI [DOI: https://dx.doi.org/10.1182/blood-2017-06-743252] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28972016][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680607]

19. Roberts, KG; Gu, Z; Payne-Turner, D et al. High frequency and poor outcome of Philadelphia Chromosome-Like acute lymphoblastic leukemia in adults. J Clin Oncol; 2017; 35, 4 pp. 394-401. [DOI: https://dx.doi.org/10.1200/JCO.2016.69.0073] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27870571]

20. Harvey, RC; Mullighan, CG; Wang, X et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood; 2010; 116, 23 pp. 4874-4884.1:CAS:528:DC%2BC3cXhs1SlsrvN [DOI: https://dx.doi.org/10.1182/blood-2009-08-239681] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20699438][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321747]

21. Hunger, SP. Integrated risk stratification using minimal residual disease and sentinel genetic alterations in pediatric acute lymphoblastic leukemia. J Clin Oncol; 2018; 36, 1 pp. 4-6. [DOI: https://dx.doi.org/10.1200/JCO.2017.76.0504] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29131700]

22. 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. Ann Hematol; 2023; 102, 6 pp. 1287-1300.1:CAS:528:DC%2BB3sXptF2gt7k%3D [DOI: https://dx.doi.org/10.1007/s00277-023-05241-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37129698][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10181978]

23. 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. J Clin Oncol; 2014; 32, 27 pp. 3012-3020.1:CAS:528:DC%2BC2cXitVClt7%2FK [DOI: https://dx.doi.org/10.1200/JCO.2014.55.4105] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25049327][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162497]

24. Shi, JG; Chen, X; Emm, T et al. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol; 2012; 52, 6 pp. 809-818.1:CAS:528:DC%2BC38XpsVKjtbY%3D [DOI: https://dx.doi.org/10.1177/0091270011405663] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21602517]

25. Kolodrubiec, J; Kozlowska, M; Irga-Jaworska, N et al. Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. Leuk Res Oct; 2022; 121, 106925.1:CAS:528:DC%2BB38XisVWrsr7L [DOI: https://dx.doi.org/10.1016/j.leukres.2022.106925]

26. Ribera, JM. Philadelphia chromosome-like acute lymphoblastic leukemia. Still a pending matter. Haematologica Jun; 2021; 1, 6 pp. 1514-1516.1:CAS:528:DC%2BB3MXhsFKlu7rL [DOI: https://dx.doi.org/10.3324/haematol.2020.270645]

27. Klein, K; Stoiber, D; Sexl, V; Witalisz-Siepracka, A. Untwining anti-tumor and immunosuppressive effects of JAK inhibitors-a strategy for hematological malignancies??. Cancers (Basel); 2021; 13, 1:CAS:528:DC%2BB3MXislehsrzM [DOI: https://dx.doi.org/10.3390/cancers13112611] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34073410]2611.

28. Niswander, LM; Loftus, JP; Lainey, E et al. Therapeutic potential of ruxolitinib and ponatinib in patients with EPOR-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia. Haematologica; 2021; 106, 10 pp. 2763-2767. [DOI: https://dx.doi.org/10.3324/haematol.2021.278697] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34196168][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485673]

29. Loh, ML; Tasian, SK; Rabin, KR et al. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a children’s oncology group phase 1 consortium study (ADVL1011). Pediatr Blood Cancer; 2015; 62, 10 pp. 1717-1724.1:CAS:528:DC%2BC2MXhsVWiurjJ [DOI: https://dx.doi.org/10.1002/pbc.25575] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25976292][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546537]

30. 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. Blood; 2012; 120, pp. 833-842.1:CAS:528:DC%2BC38XhtFOgurrJ [DOI: https://dx.doi.org/10.1182/blood-2011-12-389932] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22685175][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412346]

31. 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. Blood; 2017; 2017–01, 2 pp. 177-187.1:CAS:528:DC%2BC2sXosVKitLw%3D [DOI: https://dx.doi.org/10.1182/blood-2016-05-707653]

32. Torrano, V; Procter, J; Cardus, P; Greaves, M; Ford, AM. ETV6-RUNX1 promotes survival of early B lineage progenitor cells via a dysregulated erythropoietin receptor. Blood Nov; 2011; 3, 18 pp. 4910-4918.1:CAS:528:DC%2BC3MXhsVOgsrnK [DOI: https://dx.doi.org/10.1182/blood-2011-05-354266]

33. Downes, CE; McClure, BJ; McDougal, DP et al. JAK2 alterations in acute lymphoblastic leukemia: molecular insights for superior precision medicine strategies. Front Cell Dev Biol; 2022; 10, 942053. [DOI: https://dx.doi.org/10.3389/fcell.2022.942053] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35903543][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315936]

34. Bayram, N; Yaman, Y; Özdilli, K et al. Clinical efficacy of ruxolitinib monotherapy and haploidentical hematopoeitic stem cell transplantation in a child with Philadelphia Chromosome-like relapsed/refractory acute lymphoblastic leukemia. Pediatr Transplant; 2021; 25, 4 e14024.1:CAS:528:DC%2BB3MXhs1yjtrnL [DOI: https://dx.doi.org/10.1111/petr.14024] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33860589]

35. Pemmaraju, N; Kantarjian, H; Kadia, T et al. A Phase I/II Study of the Janus Kinase (JAK)1 and 2 Inhibitor Ruxolitinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk; 2015; 15, 3 pp. 171-176. [DOI: https://dx.doi.org/10.1016/j.clml.2014.08.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25441108]

36. Mascarenhas, J. A Concise Update on Risk Factors, Therapy, and Outcome of Leukemic Transformation of Myeloproliferative Neoplasms. Clin Lymphoma Myeloma Leuk; 2016; 16, Suppl pp. S124-129. [DOI: https://dx.doi.org/10.1016/j.clml.2016.02.016] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27521308]

37. Quintas-Cardama, A; Vaddi, K; Liu, P et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood; 2010; 115, 15 pp. 3109-3117.1:CAS:528:DC%2BC3cXltlWqsr8%3D [DOI: https://dx.doi.org/10.1182/blood-2009-04-214957] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20130243][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953826]

38. Quintas-Cardama, A; Kantarjian, H; Cortes, J; Verstovsek, S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov; 2011; 10, 2 pp. 127-140.1:CAS:528:DC%2BC3MXhtleksrg%3D [DOI: https://dx.doi.org/10.1038/nrd3264] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21283107]

39. Verstovsek, S; Mesa, RA; Gotlib, J et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol; 2017; 10, 1:CAS:528:DC%2BC1cXksl2ht7Y%3D [DOI: https://dx.doi.org/10.1186/s13045-017-0417-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28228106][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322633]55.

40. Ruxolitinib Phosphate. Am J Health Syst Pharm Jan; 2022; 5, 2 pp. 6-9. [DOI: https://dx.doi.org/10.1093/ajhp/zxab396]

41. Kantarjian, H; Stein, A; Gokbuget, N et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med; 2017; 376, 9 pp. 836-847.1:CAS:528:DC%2BC2sXhtlyktbjL [DOI: https://dx.doi.org/10.1056/NEJMoa1609783] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28249141][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881572]

42. Gokbuget, N; Dombret, H; Bonifacio, M et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood; 2018; 131, 14 pp. 1522-1531.1:CAS:528:DC%2BC1cXhvVemsb3P [DOI: https://dx.doi.org/10.1182/blood-2017-08-798322] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29358182][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027091]

43. Park, JH; Riviere, I; Gonen, M et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med; 2018; 378, 5 pp. 449-459.1:CAS:528:DC%2BC1cXitlylsbY%3D [DOI: https://dx.doi.org/10.1056/NEJMoa1709919] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29385376][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637939]

44. Xu, GF; Liu, LM; Wang, M et al. Treatments of Ph-like acute lymphoblastic leukemia: a real-world retrospective analysis from a single large center in China. Leuk Lymphoma; 2022; 63, 11 pp. 2652-2662.1:CAS:528:DC%2BB38Xhslamt7rP [DOI: https://dx.doi.org/10.1080/10428194.2022.2090550] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35748683]