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Ph-like ALL
with an overlapping group of hyperploid cytogenetics and Ph-like ALL.11,28 A recent comprehensive and integra- tive genomic classification of B-ALL categorized 23 leukemia subclasses, clearly defined by a specific genetic aberration, thus minimizing overlaps with the Ph-like phenotype.29
There is no consensus approach to the diagnosis of patients who express a Ph-like gene signature.30 These patients usually present with a higher white blood cell count1,4,17,22,27,31 and are likely to remain MRD-positive fol- lowing standard induction regimens.4,13,14,22,28,31 Selecting an optimal screening method and defining the patient popu- lation to be screened are still moving targets.
When first recognized, Ph-like ALL were retrospectively identified based upon gene expression profiling of a very wide array of genes.1,4,32 Notably, two large gene arrays,1,4 using a 257-gene probe set and a 110-gene set2 shared only a minimal number of genes. Application of both arrays to each of two different cohorts of patients resulted in low concordance.2 Remarkably, kinase fusion cases in the two cohorts were identified by both methods in complete con- cordance, while there were many cases of high expression of CRLF2 and JAK/STAT mutations that were recognized with the 257-gene probe set and not with the 110-gene set.2 Thus, while the evaluation of newly diagnosed "B- cell other" ALL patients should include an attempt to iden- tify the Ph-like phenotype,33 a definitive diagnosis should not rely on the gene expression phenotype but rather on the identification of a genetic aberration in the cell signal- ing related gene. RNA sequencing enables both identifica- tion of a Ph-like phenotype and comprehensive analysis of aberrant translocations. As this method is technically complicated and unavailable in most centers, a routine diagnosis of Ph-like ALL requires a combination of a sim- ple screening test and an ultimate method to identify the culprit leukemia driver in each patient.
One screening approach is to search for a specific phe- notype using limited sets of genes.34 Alternatively, a panel of FISH probes or polymerase chain reaction (PCR) tests covering the most common ABL, JAK/EPOR and CRLF2 translocations can be employed as a screening tool.27,35 Low density microarrays (LDA), using a limited number of genes were first employed by Harvey et al.36 With an array of only 15 genes the tests were highly sensitive and specific (93% and 89%, respectively) for the identification of Ph-like ALL. The concordance between this assay and the result of the original 257-gene set analysis was only 87%, mainly due to over-diagnosis of cases of high CRLF2 expression by the LDA. Application of this method in high-risk pediatric ALL patients failed to detect mutations in about 15% of LDA-positive patients.15 Interestingly, the study identified nine patients with CRLF2 translocations who were LDA-negative, which translated into a false negative value of less than 1%. Other LDA with fewer genes were developed by Heatley et al.18 and Roberts et al.37 To simplify this approach, Chiaretti et al. used quanti- tative real-time PCR to assess expression levels of ten genes and create a Ph-like ALL predictor.27 Expression- based screening methods identify a phenotype and should be followed by a search for a targetable genotype, either by RNA sequencing, whole exome or targeted PCR panel sequencing, or by multiple-probe FISH analysis. As men- tioned above, false negative results are rare; however, there are a substantial number of cases presenting with an overexpression signature but with no detectable driver
genetic aberration. The actual risk and clinical implica- tions in such cases are unknown.
It is also possible to screen for Ph-like ALL by searching directly for specific translocations and mutations. In a study conducted by the research group from the Munich Leukemia Laboratory in Germany38 screening by multiple FISH probes and targeted PCR (ABL1, ABL2, CSF1R, PDGFRB along with quantitative PCR for CRLF2) success- fully identified all patients who had a Ph-like gene expres- sion profile according to the aforementioned 257-gene set. Another advantage of this method is the option of using quantitative PCR of the found driver mutation for MRD detection, although the negative predictive value of each aberration should be evaluated separately. Cooperative groups and leading centers around the world use different methods for the identification of Ph-like ALL. In Europe, some groups employ multiplex PCR or commercially avail- able targeted RNA sequencing kits, while others use a FISH panel for primary screening. In the USA, the Children's Oncology Group (COG) uses LDA as the screening approach. Comprehensive RNA sequencing is conducted only in specific centers such as the St. Jude Medical Center.
The variability of the methods available makes the diag- nosis of a Ph-like expression signature in a patient with no defined genetic alteration a challenge. Figure 1 presents a suggested clinical screening algorithm for Ph-like ALL to be applied outside of clinical trials.
Treatment of Philadelphia chromosome-like acute lymphoblastic leukemia
To illustrate some of the key therapeutic issues and dilemmas in Ph-like ALL, we present and discuss several case scenarios. The discussion focuses on possible benefits of induction therapy intensification for these patients, post-induction treatment in MRD-positive and -negative patients as well as management of the most challenging cases of relapsed and elderly patients.
Is there any preferred induction regimen for patients presenting with Philadelphia chromosome-like acute lymphoblastic leukemia?
Case presentation. A 57-year old previously healthy man diagnosed with pre-B ALL has just been transferred from a rural hospital to your center. His peripheral blast count at diagnosis was 32x109 cells/L which dropped significantly after 1 week of steroid therapy. FISH panel analysis identified the EPOR translocation as the sole cytogenetic aberration. What are prefer- able induction therapy options?
Remission induction protocols commonly employed in ALL are variations of a consensus basic paradigm, combin- ing four or five of the following drugs: anthracyclines, vin- cristine, cyclophosphamide, L/PEG-asparaginase and steroids. Differences between the protocols lie in their intensity, schedule and the addition of 6-mercaptopurine, cytarabine and rituximab. Data derived from randomized comparisons are scanty and inconclusive regarding sur- vival superiority following any induction regimen, despite variations in remission rates in specific subgroups.39-41 In current clinical practice, appropriate treatment intensity and chemotherapy doses are usually determined based on the risk of adverse events and not on disease characteris- tics. Thus, a patient's advanced age, co-morbidities and/or fragility would lead most physicians to prescribe
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