New genetic abnormalities affecting risk assessment and patient stratification have been reported in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) defining novel subtypes. Some of these subtypes have been included in the most recent World Health Organization classification.1 Almost 10 years ago, two independent studies identified a subset of pediatric ALL characterized by a specific gene expression profile similar to that of Philadelphia (Ph) chromosome-positive ALL.2,3 This novel ALL subtype, called Ph-like ALL or BCR-ABL1-like ALL, is a frequent ALL subtype that comprises up to 15% of pediatric BCP-ALL. Its incidence reaches 25% in adolescents and young adults and 20% in adults and it is generally recognized as being associated with a poor prognosis at any age.4
Ph-like ALL is characterized by multiple genetic aberrations that converge on tyrosine kinase and cytokine receptor signaling pathways.5 According to the signaling pathway involved several subgroups have been defined. These include CRLF2 rearrangements or mutations, fusions involving ABL-class genes, Ras signaling pathways and other less common fusions. Alterations in the CRLF2 gene are the most frequent and result in overexpression of this gene and an increase of CRLF2 protein expression. Aberrant CRLF2 expression frequently cooccurs with JAK activating mutations or other mutations deregulating JAK/STAT signaling (e.g., IL7R mutations). Deregulation of JAK/STAT signaling may also be due to JAK2 or EPOR rearrangements or additional alterations activating other JAK/STAT signaling genes. In turn, the subgroup of ABL-class fusions involving ABL1, ABL2, CSF1R and PDGFRB accounts for 15-20% of Ph-like ALL cases.
Since kinase-activating alterations are frequent in Phlike ALL and most converge on clinically actionable signaling, there is great interest in the early identification of Ph-like patients, with the aim of improving the prognosis with the use of tyrosine kinase inhibitors (TKI). However, identification of Ph-like ALL is currently challenging, and appropriate assays are not yet available for use as routine diagnostic approaches.6
In this issue of Haematologica, Chiaretti et al. screened 88 BCP-ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2A) enrolled in the pediatric-inspired, measurable residual disease (MRD)-driven GIMEMA LAL1913 front-line protocol for adults with Ph-negative ALL in order to assess response to the treatment and prognosis.7 Twenty-eight of these 88 cases (31.8%) showed the Ph-like phenotype. Screening for Ph-like ALL was performed successfully using the “BCR/ABL1-like predictor” developed by the GIMEMA Group.8 This model is based on the identification of nine genes specifically overexpressed by adult Phlike ALL cases and uses their expression values together with CRLF2 transcript quantification by real time quantitative polymerase chain reaction to build this predictive tool. This study showed that Ph-like patients had a lower complete response rate, event-free survival and diseasefree survival, as well as greater MRD persistence when treated with a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing the contention that early recognition of Ph-like ALL is crucial to refine risk-stratification and optimize therapeutic strategies. While some conflicting results on the prognosis of Ph-like ALL have been reported in pediatric patients, the results of this study are concordant with those of other studies performed in adults, uniformly showing a poor prognosis for this ALL subtype.4,9,10 An important finding of this study is the correlation between the Ph-like phenotype and the poor MRD clearance at all the time points analyzed, but especially at week 10 of the protocol, a time point used for the decision to proceed or not to hematopoietic stem cell transplantation (HSCT) in this trial. In fact, the Ph-like profile proved to be the only risk factor for MRD positivity at this time point. This finding is relevant since half of the patients were considered a priori as standard risk according to their features at baseline. In addition, Ph-like ALL patients from this trial showed inferior cytologic complete response after induction therapy (a feature not shown in all studies)11 indicating that better induction therapies are needed for these patients. This study also suggests that HSCT is beneficial in these cases and should be pursued at the earliest opportunity in order to increase event-free survival.
It seems clear that apart from early recognition, the management of Ph-like ALL patients should be optimized, and many efforts are currently addressed to improve the results of therapy. These efforts are mainly focused on the incorporation of targeted therapies and immunotherapy to the chemotherapy schedules. TKI inhibitors (e.g., imatinib, dasatinib and ruxolitinib), histone deacetylase inhibitors (e.g., chidamide) and bispecific monoclonal antibodies (e.g., blinatumomab) are the compounds most frequently evaluated in clinical trials (Table 1). However, there is scarce information available on the results of these approaches. As an example, a recent retrospective report by Tanasi et al. showed that the introduction of TKI frontline during consolidation improved MRD-negative status and was associated with a 3-year OS of 77% in a small series of 24 adult patients.12
Clinical trials are limited in Ph-like ALL. Regarding pediatric trials, in the ongoing trials of the Children’s Oncology Group (COG) (clinicaltrials gov. Identifier: NCT028830499 and in the Total Therapy XVII trial of the Saint Jude Children’s Research Hospital [SJCRH] clinicaltrials gov. Identifier: NCT03117751),13 patients with National Cancer Institute (NCI) high-risk characteristics or poor early MRD response, who are positive for ABL class fusions and JAK pathway mutations, receive dasatinib and ruxolitinib, respectively, together with conventional frontline chemotherapy from consolidation until the end of maintenance therapy. The COG ALL1521 trial (clinicaltrials gov. Identifier: NCT02723994) is investigating the benefit of adding ruxolitinib to backbone COG based NCI high-risk chemotherapy for patients with CRLF2-rearranged ALL. In the study by the European ALLTogether consortium, patients with ABL-class fusions at diagnosis receive TKI on top of chemotherapy from day 15 of induction; HSCT is indicated in cases with poor MRD response. In the French CALL-F01 protocol (clinicaltrials gov. Identifier: NCT02716233), RNA sequencing is performed in all Bother ALL in case of induction failure or MRD positivity. Imatinib is given in combination with chemotherapy in the high-risk group, and HSCT is indicated in poor responders. The early introduction of TKI in addition to chemotherapy in ABL-class positive BCP-ALL is planned to be evaluated within an intercontinental collaborative trial (clinicaltrials gov. Identifier: NCT03007147) involving the COG and EsPhALL (European PhALL Consortium) groups.
Clinical trials for AYA and adult patients are even more limited. Phase I/II trials conducted at the MD Anderson Cancer Center are testing dasatinib or low doses of ruxolitinib in combination with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in relapsed/refractory ALL and ABL-class fusions or CRLF2/JAK mutations, respectively. Interim data analysis has demonstrated the safety of these combinations with limited efficacy.9 A recent phase I trial at the University of Chicago and other institutions is studying ruxolitinib in combination with the pediatric-inspired CALBG (Cancer and Acute Leukemia Group B) 10403 chemotherapy regimen in adolescents with newly diagnosed Ph-like ALL harboring CRLF2/JAK alterations, with a planned phase II expansion study if safety is demonstrated.
Regarding the election of TKI, there is no clear evidence of the superiority of dasatinib over imatinib for Ph-like ALL cases with ABL-class fusions. This comparison is especially difficult given that the doses of these TKI differ among trials. Other TKI, such as nilotinib, bosutinib and ponatinib, are still being investigated as phase I and II trials in pediatric cancers. Since the combination of TKI and immunotherapy with blinatumomab has proven feasible and effective in patients with Ph-positive ALL,14 this approach should be explored in patients with Ph-like ALL together with reduced-intensity chemotherapy and HSCT.15,16
There are challenges in the diagnosis of Ph-like ALL before using targeted therapy in frontline treatment. Diagnostic technologies such as RNA sequencing and similar strategies should be implemented in a timely fashion for all “B-other ALL”, but to date appropriate assays are not yet available as widely recognized diagnostic approaches.17-19 Furthermore, although ABL-class and JAKpathway alterations account for most Ph-like ALL cases, there are also several alterations involving kinases that are not inhibited by either TKI or JAK inhibitors. For this subgroup of Ph-like cases without known targetable lesions innovative therapies such as immunotherapy could be useful to reduce the MRD level before MRD-guided HSCT.20 Nonetheless, all these efforts will undoubtedly require collaborative international approaches to conduct successful studies.
No conflicts of interest to disclose.
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