Editorials Philadelphia chromosome-like acute lymphoblastic leukemia. Still a pending matter Josep-Maria Ribera Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona and Universitat Autònoma de Barcelona, Spain E-mail: JOSEP-MARIA RIBERA - jribera@iconcologia.net doi:10.3324/haematol.2020.270645 N ew genetic abnormalities affecting risk assess- activating other JAK/STAT signaling genes. In turn, the ment and patient stratification have been reported subgroup of ABL-class fusions involving ABL1, ABL2, in B-cell precursor (BCP) acute lymphoblastic CSF1R and PDGFRB accounts for 15-20% of Ph-like ALL leukemia (ALL) defining novel subtypes. Some of these cases. subtypes have been included in the most recent World Since kinase-activating alterations are frequent in Ph- Health Organization classification.1 Almost 10 years ago, like ALL and most converge on clinically actionable sig- two independent studies identified a subset of pediatric naling, there is great interest in the early identification of ALL characterized by a specific gene expression profile Ph-like patients, with the aim of improving the prognosis similar to that of Philadelphia (Ph) chromosome-positive with the use of tyrosine kinase inhibitors (TKI). However, ALL.2,3 This novel ALL subtype, called Ph-like ALL or identification of Ph-like ALL is currently challenging, and BCR-ABL1-like ALL, is a frequent ALL subtype that com- appropriate assays are not yet available for use as routine prises up to 15% of pediatric BCP-ALL. Its incidence diagnostic approaches.6 reaches 25% in adolescents and young adults and 20% in In this issue of Haematologica, Chiaretti et al. screened adults and it is generally recognized as being associated 88 BCP-ALL cases negative for the major fusion genes with a poor prognosis at any age.4 (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2A) Ph-like ALL is characterized by multiple genetic aberra- enrolled in the pediatric-inspired, measurable residual dis- tions that converge on tyrosine kinase and cytokine ease (MRD)-driven GIMEMA LAL1913 front-line proto- receptor signaling pathways.5 According to the signaling col for adults with Ph-negative ALL in order to assess pathway involved several subgroups have been defined. response to the treatment and prognosis.7 Twenty-eight These include CRLF2 rearrangements or mutations, of these 88 cases (31.8%) showed the Ph-like phenotype. fusions involving ABL-class genes, Ras signaling path- Screening for Ph-like ALL was performed successfully ways and other less common fusions. Alterations in the using the “BCR/ABL1-like predictor” developed by the CRLF2 gene are the most frequent and result in overex- GIMEMA Group.8 This model is based on the identifica- pression of this gene and an increase of CRLF2 protein tion of nine genes specifically overexpressed by adult Ph- expression. Aberrant CRLF2 expression frequently co- like ALL cases and uses their expression values together occurs with JAK activating mutations or other mutations with CRLF2 transcript quantification by real time quanti- deregulating JAK/STAT signaling (e.g., IL7R mutations). tative polymerase chain reaction to build this predictive Deregulation of JAK/STAT signaling may also be due to tool. This study showed that Ph-like patients had a lower JAK2 or EPOR rearrangements or additional alterations complete response rate, event-free survival and disease- Table 1. Clinical trials either specific for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL patients) or including patients with Ph-like ALL*. NCT number Group Schedule Phase N patients Age (yrs) Status planned or enrolled 02883049 COG Dasatinib 3 5,956 1-30 Active, not recruiting Ruxolitinib 02723994 COG Ruxolitinib 2 170 1-21 Recruiting 03117751 SJCRH Dasatinib 2/3 1,000 1-18 Recruiting Ruxolitinib 02420717 MDACC Dasatinib Ruxolitinib 2 92 ≥10 Active, not recruiting 03571321 University of Chicago Ruxolitinib 1 15 18-39 Recruiting 03643276 AIEOP/BFM Bortezomib 3 5,000 ≤17 Recruiting Blinatumomab 02716233 Assistance Publique - Imatinib 3 1,578 1-18 Recruiting Hôpitaux de Paris 03007147 COG Imatinib 3 700 2-21 Recruiting EsPhALL 03564470 Nanfang Hospital Chidamide 2 120 14-55 Unknown Guangzhou Dasatinib *Clinicaltrials .gov. accessed on November 28, 2020. COG: Children’s Oncology Group; SJCRH: Saint Jude Childrens Research Hospital; MDACC: MD Anderson Cancer Center; AIEOP: Associazione Italiana di Ematologia e Oncologia Pediatrica; BFM: Berlin-Frankfurt-Münster; EsPhALL: European PhALL Consortium; yrs: years. 1514 haematologica | 2021; 106(6) Editorials free survival, as well as greater MRD persistence when CALL-F01 protocol (clinicaltrials gov. Identifier: treated with a pediatric-oriented and MRD-driven adult NCT02716233), RNA sequencing is performed in all B- ALL protocol, thus reinforcing the contention that early other ALL in case of induction failure or MRD positivity. recognition of Ph-like ALL is crucial to refine risk-stratifi- Imatinib is given in combination with chemotherapy in the cation and optimize therapeutic strategies. While some high-risk group, and HSCT is indicated in poor responders. conflicting results on the prognosis of Ph-like ALL have The early introduction of TKI in addition to chemotherapy been reported in pediatric patients, the results of this in ABL-class positive BCP-ALL is planned to be evaluated study are concordant with those of other studies per- within an intercontinental collaborative trial (clinicaltrials formed in adults, uniformly showing a poor prognosis for gov. Identifier: NCT03007147) involving the COG and this ALL subtype.4,9,10 An important finding of this study is EsPhALL (European PhALL Consortium) groups. the correlation between the Ph-like phenotype and the Clinical trials for AYA and adult patients are even more poor MRD clearance at all the time points analyzed, but limited. Phase I/II trials conducted at the MD Anderson especially at week 10 of the protocol, a time point used Cancer Center are testing dasatinib or low doses of rux- for the decision to proceed or not to hematopoietic stem olitinib in combination with hyper-CVAD (cyclophos- cell transplantation (HSCT) in this trial. In fact, the Ph-like phamide, vincristine, doxorubicin, and dexamethasone) profile proved to be the only risk factor for MRD positiv- in relapsed/refractory ALL and ABL-class fusions or ity at this time point. This finding is relevant since half of CRLF2/JAK mutations, respectively. Interim data analysis the patients were considered a priori as standard risk has demonstrated the safety of these combinations with according to their features at baseline. In addition, Ph-like limited efficacy.9 A recent phase I trial at the University of ALL patients from this trial showed inferior cytologic Chicago and other institutions is studying ruxolitinib in complete response after induction therapy (a feature not combination with the pediatric-inspired CALBG (Cancer shown in all studies)11 indicating that better induction and Acute Leukemia Group B) 10403 chemotherapy regi- therapies are needed for these patients. This study also men in adolescents with newly diagnosed Ph-like ALL suggests that HSCT is beneficial in these cases and should harboring CRLF2/JAK alterations, with a planned phase II be pursued at the earliest opportunity in order to increase expansion study if safety is demonstrated. event-free survival. Regarding the election of TKI, there is no clear evidence It seems clear that apart from early recognition, the of the superiority of dasatinib over imatinib for Ph-like management of Ph-like ALL patients should be opti- ALL cases with ABL-class fusions. This comparison is mized, and many efforts are currently addressed to especially difficult given that the doses of these TKI differ improve the results of therapy. These efforts are mainly among trials. Other TKI, such as nilotinib, bosutinib and focused on the incorporation of targeted therapies and ponatinib, are still being investigated as phase I and II tri- immunotherapy to the chemotherapy schedules. TKI als in pediatric cancers. Since the combination of TKI and inhibitors (e.g., imatinib, dasatinib and ruxolitinib), his- immunotherapy with blinatumomab has proven feasible tone deacetylase inhibitors (e.g., chidamide) and bispecif- and effective in patients with Ph-positive ALL,14 this ic monoclonal antibodies (e.g., blinatumomab) are the approach should be explored in patients with Ph-like ALL compounds most frequently evaluated in clinical trials together with reduced-intensity chemotherapy and (Table 1). However, there is scarce information available HSCT.15,16 on the results of these approaches. As an example, a There are challenges in the diagnosis of Ph-like ALL recent retrospective report by Tanasi et al. showed that before using targeted therapy in frontline treatment. the introduction of TKI frontline during consolidation Diagnostic technologies such as RNA sequencing and improved MRD-negative status and was associated with similar strategies should be implemented in a timely fash- a 3-year OS of 77% in a small series of 24 adult patients.12 ion for all “B-other ALL”, but to date appropriate assays Clinical trials are limited in Ph-like ALL. Regarding pedi- are not yet available as widely recognized diagnostic atric trials, in the ongoing trials of the Children’s Oncology approaches.17-19 Furthermore, although ABL-class and JAK- Group (COG) (clinicaltrials gov. Identifier: NCT028830499 pathway alterations account for most Ph-like ALL cases, and in the Total Therapy XVII trial of the Saint Jude there are also several alterations involving kinases that are Children’s Research Hospital [SJCRH] clinicaltrials gov. not inhibited by either TKI or JAK inhibitors. For this sub- Identifier: NCT03117751),13 patients with National Cancer group of Ph-like cases without known targetable lesions Institute (NCI) high-risk characteristics or poor early MRD innovative therapies such as immunotherapy could be response, who are positive for ABL class fusions and JAK useful to reduce the MRD level before MRD-guided pathway mutations, receive dasatinib and ruxolitinib, HSCT.20 Nonetheless, all these efforts will undoubtedly respectively, together with conventional frontline require collaborative international approaches to conduct chemotherapy from consolidation until the end of mainte- successful studies. nance therapy. The COG ALL1521 trial (clinicaltrials gov. Identifier: NCT02723994) is investigating the benefit of Disclosures adding ruxolitinib to backbone COG based NCI high-risk No conflicts of interest to disclose. chemotherapy for patients with CRLF2-rearranged ALL. In the study by the European ALLTogether consortium, Funding patients with ABL-class fusions at diagnosis receive TKI on J-MR is supported in part by grant 2017 SGR288 (GRC) top of chemotherapy from day 15 of induction; HSCT is Generalitat de Catalunya and an unrestricted grant from “La indicated in cases with poor MRD response. In the French Caixa” Foundation. haematologica | 2021; 106(6) 1515 Editorials References 11. Herold T, Schneider S, Metzeler KH, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have 1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the IGH-CRLF2 and JAK2 mutations, persistence of minimal residual World Health Organization classification of myeloid neoplasms and disease and poor prognosis. Haematologica. 2017;102(1):130-138. acute leukemia. Blood. 2016;127(20):2391-405. 12. Tanasi I, Ba I, Sirvent N, et al. Efficacy of tyrosine kinase inhibitors 2. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype in Ph-like acute lymphoblastic leukemia harboring ABL-class of childhood acute lymphoblastic leukaemia with poor treatment rearrangements. Blood. 2019;134(16):1351-1355. outcome: a genome-wide classification study. Lancet Oncol. 13. Pui CH, Roberts KG, Yang JJ, Mullighan CG. Philadelphia chromo- 2009;10(2):125-34. some-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma 3. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis Leuk. 2017;17(8):464-470. in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-80. 14. Foà R, Bassan R, Vitale A, et al. Dasatinib-Blinatumomab for Ph- 4. Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. outcome of Philadelphia chromosome-like acute lymphoblastic 2020;383(17):1613-1623. leukemia in adults. J Clin Oncol. 2017;35(4):394-401. 15. Harvey RC, Tasian SK. Clinical diagnostics, and treatment strategies 5. Tasian SK, Loh ML, Hunger SP. Philadelphia chromosome-like acute for Philadelphia chromosome-like acute lymphoblastic leukemia. lymphoblastic leukemia. Blood. 2017;130(19):2064-2072. Blood Adv. 2020;4(1):218-228. 6. Boer JM, Marchante JR, Evans WE, et al. BCR-ABL1-like cases in 16. Cario G, Leoni V, Conter V, Baruchel A, Schrappe M, Biondi A. BCR- pediatric acute lymphoblastic leukemia: a comparison between ABL1-like acute lymphoblastic leukemia in childhood and targeted DCOG/Erasmus MC and COG/St. Jude signatures. Haematologica. therapy. Haematologica. 2020;105(9):207019. 2015;100(9): e354-7 17. Brown LM, Lonsdale A, Zhu A, et al. The application of RNA 7. Chiaretti S, Messina M, Della Starza I, et al. BCR-ABL1-like is asso- sequencing for the diagnosis and genomic classification of pediatric ciated with MRD persistence and poor outcome. First report of the acute lymphoblastic leukemia. Blood Adv. 2020;4(5):930-942. MRD-oriented GIMEMA 1913. Haematologica 2020. doi: 18. Anagnostou T, Knudson RA, Pearce KE, et al. Clinical utility of fluo- 10.3324/haematol.2020.247973 rescence in situ hybridization-based diagnosis of BCR-ABL1 like 8. Chiaretti S, Messina M, Grammatico S, et al. Rapid identification of (Philadelphia chromosome like) B-acute lymphoblastic leukemia. BCR/ABL1-like acute lymphoblastic leukaemia patients using a pre- Am J Hematol. 2020;95(3):e68-E72. dictive statistical model based on quantitative real time-polymerase 19. Sánchez R, Ribera J, Morgades M, et al. A novel targeted RNA-Seq chain reaction: clinical, prognostic and therapeutic implications. Br J panel identifies a subset of adult patients with acute lymphoblastic Haematol. 2018;181(5):642-652. leukemia with BCR-ABL1-like characteristics. Blood Cancer J. 9. Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic 2020;10(4):43. doi: 10.1038/s41408-020-0308-3. leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572-581. 20. El Fakih R, Savani B, Mohty M, Aljurf M. Hematopoietic cell trans- 10. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older plant consideration for Philadelphia chromosome-like acute lym- adolescents and young adults with acute lymphoblastic leukemia: phoblastic leukemia patients. Biol Blood Marrow Transplant. results of CALGB 10403. Blood. 2019;133(14):1548-1559. 2020;26(1):e16-e20. Granulocyte colony-stimulating factor acts on lymphoid-biased, short-term hematopoietic stem cells Yulin Chen and K. Lenhard Rudolph Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Research Group on Stem Cell Aging, Jena and Medical Faculty, University Hospital Jena (UKJ), Jena, Germany E-mail: K. LENHARD RUDOLPH - lenhard.rudolph@leibniz-fli.de doi:10.3324/haematol.2020.271205 G ranulocyte colony-stimulating factor (G-CSF) is a enhancement of early lymphopoiesis of bone marrow cytokine that increases myelopoiesis,1 impairs lym- stem and progenitor cells after exposure to G-CSF.7 In phopoiesis by inhibiting committed progenitor contrast, however, G-CSF is also known to instruct bone cells,2,3 and enhances hematopoietic stem cell (HSC) mobi- marrow stromal cells to suppress the function of commit- lization.4 The direct effects of G-CSF on purified subpopu- ted progenitors of B-lymphopoiesis.2 The functional rele- lation of HSC remained to be delineated. In this issue of vance of the G-CSF-mediated priming of early lymphoid Haematologica, Xie et al.5 investigate the influence of G-CSF progenitor cells and lymphoid-biased HSC5,7 in associa- on proliferation and the repopulating potential of myeloid- tion with G-CSF-mediated impairment in the progression biased, long-term HSC (CD201+CD150+CD48–CD41– of lymphopoiesis from committed progenitor cells2 CD34–KSL) and lymphoid-biased, short-term HSC should be delineated in future studies. (CD201+CD150–CD48–CD41–CD34–KSL). The primary role of G-CSF is currently seen in activa- Understanding the direct influences of G-CSF on HSC tion of myelopoiesis to strengthen myeloid immune could improve our understanding of HSC responses to an responses, such as the recruitment of neutrophils during increase in G-CSF level caused by inflammation.6 The bacterial lung infections.8 However, the simultaneous study by Xie et al. shows that G-CSF acts directly on lym- priming of early lymphoid progenitor cells and lymphoid- phoid-biased, short-term HSC but not on myeloid-biased biased HSC by G-CSF may also be important to ensure HSC. Interestingly, G-CSF cooperates with stem cell fac- prompt reactivation of lymphopoiesis after the initial tor in driving the expansion of lymphoid-biased, short- induction of myeloid cell-driven immune responses. The term HSC in culture and in maintaining the in vivo repop- sequential coordination of such immune actions by G- ulating potential of such cultures. These findings suggest CSF seems to be an interesting area of future research. that G-CSF-mediated effects on lymphoid-biased, short- Understanding direct influences of G-CSF on HSC term HSC may contribute to the previously noted could also be relevant for our understanding of HSC 1516 haematologica | 2021; 106(6)