Abstract
Background
BCR-ABL1-like acute lymphoblastic leukaemia (ALL) represents a perplexing subclass of ALL mainly due to genomic heterogeneity and non-availability of standardized diagnostic tests. The data on prevalence, clinical–haematological profile and outcome are limited, more so from low-middle income countries.
Methods
This prospective observational study enrolled children<14 years with B-ALL. Recurrent genetic/chromosomal aberrations were excluded. BCR-ABL1-like aberrations were analysed using Polymerized Chain Reaction (PCR) or Next-Generation Sequencing (NGS). Two groups with/without BCR-ABL1-like ALL (Mut+/Mut-) were compared.
Results
Out of 214 eligible children; 75 with “B-other ALL” were analysed for BCR-ABL1-like aberrations. Their prevalence was 34/214 (15.8%) in B-ALL and 34/75 (45.3%) in “B-other” ALL (PCR:33.3% and NGS:53.3%). Majority of the aberrations were JAK2E16 and ILR7e5/ILR7e6 with PCR and RAS pathway and PAX5 fusion with NGS. Baseline demographic, clinical and laboratory parameters including aberrant flowcytometry were comparable in Mut+ and Mut-groups. Children with day-8 absolute blast count (ABC) were higher in Mut+ group. High end-induction minimal residual disease (MRD) was comparable in two groups. Number of NCI-standard risk (SR) at diagnosis with high D-8 ABC or high MRD was higher in Mut+ group. Similar results were found when aberrations were analysed by NGS alone. In all 56 children are alive, 19 had an event (relapse/death). The outcomes were comparable in two groups with median follow-up of 1075 days (IQR: 660–1527); when analysis was based on combined as well as NGS-based methodology alone.
Conclusions
We report 15.8% prevalence of BCR-ABL1-like ALL in children by PCR or NGS. High D-8 ABC was associated with BCR-ABL1-like ALL with no impact on outcomes.
Keywords: BCR-ABL1-like, “B-Other” ALL, Acute lymphoblastic leukaemia, Children, Targeted sequencing
Introduction
Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. B-lineage ALL (B-ALL) is the commonest subtype and accounts for more than 80% of paediatric ALL. Traditionally, structural aberration such as t(12:21) (ETV6-RUNX1), t(9:22) (BCR-ABL1), t(1:19) (TCF3-PBX1) and 11q23 (MLL) rearrangements; and numerical chromosomal aberrations like hypodiploidy and hyperdiploidy form the prognostic panel for ALL and are termed as common recurrent cytogenetic abnormalities (RCA). RCA constitutes around two-thirds of molecular abnormalities in paediatric ALL. Rest of the paediatric ALL is broadly classified as “B-other ALL”. Collaborative group studies have further refined the above molecular classification of ALL, thereby opening avenues for personalized treatment by identifying newer targets for therapeutic interventions.1
Relapses occur in around 15–20% of children treated for ALL, suggesting further studies to understand disease biology by unravelling the complete genetic signature of ALL.1,2 Advances in genomics in recent times have helped in understanding novel genetic aberrations including BCR-ABL1-like ALL, which is defined as B-ALL group which expresses the BCR-ABL signature in absence of BCR-ABL fusion. It lacks common RCA seen in B-ALL and is classified under “B-other” ALL.3,4 It is characterized by various genomic signatures based on prediction analysis of microarrays (PAM) and hierarchal clustering (HC) that activate kinases and deregulate cytokine receptor signalling.5,6 Majority of BCR-ABL1-like cases have aberrations in genes involved in B-cell development, like IKAROS (IKZF1), E2A (TCF3), EBF1, PAX5 and rearrangements including ABL1, JAK2, PDGFRB, CRLF2 and EPOR and activating mutations of IL7R and FLT3. Several of these alterations are liable to be attenuated with targeted therapy, thereby improving treatment outcomes.7,8
High total leucocyte count (TLC) at diagnosis and indicators of non-response to therapy like positive end-induction minimal residual disease (MRD) are the only consistent indicators of BCR-ABL1-like ALL.9 It has a pooled prevalence of 15–26% in B-ALL and 50% in “B-other” ALL class, across age-groups.7,10 It is associated with higher drug resistance, high relapse rates and poor outcomes. The pooled 5-year overall survival (OS), disease-free survival, event-free survival (EFS) and cumulative incidence of relapse (CIR) being 42.8%, 23.3%, 37.3% and 52.9% respectively.10
In view of the non-availability of an optimal screening method; diverse methods for detection of BCR-ABL1-like aberrations including multiplex polymerised chain reaction (PCR), low-density microarrays (LDA), fluorescence in-situ hybridization (FISH), and more recently targeted sequencing by Next-generation sequencing (NGS) are used.8,11 In low-middle income countries (LMIC), the diagnosis of these aberrations is further plagued by non-availability and economic viability. There is a paucity of literature on BCR-ABL1-like ALL from LMIC. We, therefore, designed this study with a primary objective of estimation of prevalence of BCR-ABL1-like mutations in newly diagnosed B-ALL and secondary objective of identifying association of clinical, lab and diagnostic flowcytometry (FCM) characteristics, early treatment non-response markers like day-8 absolute blast count (D-8 ABC) and end-induction MRD positivity with BCR-ABL1-like ALL; and their short-term outcomes.
Material and Methods
Participants
It was a prospective observational study conducted in a tertiary care multispecialty hospital in North India from Jan 2019 to Dec 2022. The study was approved by institutional ethics committee. The patients were enrolled after informed consent was taken from patients and/or guardians. All good clinical practice guidelines as per declaration of Helsinki were followed. All newly diagnosed cases of B-ALL<14 years of age were consecutively enrolled. B-ALL with structural translocations like t(4:11), t(1:19), t(12:21) or t(9;22) and/or chromosomal aberrations like hypodiploidy (≤44 chromosomes) or hyperdiploidy (≥51 chromosomes) were excluded.
Sample size calculation
Considering strength of our clientele to be approximately 25,00,000 with existing fertility rate of 2.18% and percentage population of children <14 years by national statistics to be 25%; total population of children <14 years in our clientele was 13,50,000.12 With annual age-standardized incidence rate of ALL being 2–4/1,00,000 in India,13 and with an established prevalence of BCR-ABL1-like ALL as 15%10 in children; the calculated sample size using Epitools software (Ausvet 2023) was 214 with 0.02 precision of estimation, assuming 80% power, 5% level of significance and 10% attrition.
Sampling and processing for BCR-ABL1-like signature analysis
Three ml sample from bone marrow/peripheral blood was collected from study participants at the time of diagnosis and bio-banked in tubes containing sodium EDTA. ALL diagnosis was based on morphology, immune phenotyping, cytogenetics and conventional karyotyping as part of routine diagnostics. After excluding common RCA as above, “B-other ALL” were analysed for BCR-ABL1-like signatures.
After extraction of genetic material (DNA and RNA) by commercial kits, cDNA was synthesized using Omniscript RT kit, Qiagen, Netherlands as per manufacturers’ instructions. The quality and quantity of extracted RNA samples were checked on NanoDrop using OD 260/280.
Sample processing methodology: 1 (PCR-based)
Real-time PCR was performed using 100 ng of cDNA with Taqman gene expression assay (Invitrogen, USA) in ABI 7500 RT-PCR system, Applied Biosystems, USA. Primers for CRLF2 (target gene) (Hs00845692_m1) and GAPDH (housekeeping reference gene) (Hs99999905_m1) were used as per manufacturers' protocol. The reaction products were analysed using ΔΔCT method, Thermofisher scientific, USA. Capillary electrophoresis was performed by genetic analyser (ABI 3130, Applied Biosystems, USA) and was analysed using Coffalyser sequence scanner software 2 v2.0 version. Normalisation of fragment peaks was performed with manufacturers’ reference probes and normal control DNA for intra-sample and inter-sample normalization. The cut-off for overexpression was taken as more than one-fold of the median value based on previous studies performed for CRLF2 overexpression. The genetic aberrations were confirmed by targeted Sanger sequencing.
Due to prevailing COVID-19 pandemic leading to non-availability of PCR kits and PCR equipment (being utilized for COVID-19 testing) and evolving molecular techniques for detection of BCR-ABL1-like genetic aberrations, the methodology was changed to Targeted Sequencing by NGS.
Sample processing methodology: 2 (NGS based)
Utilizing genomic DNA and RNA, targeted gene capture was executed employing a custom capture kit, followed by the meticulous preparation of RNA transcriptome libraries adhering to established protocols. After quality control validation, libraries were subjected to high-depth sequencing (>250X for DNA libraries and >500X for RNA libraries) on a validated Illumina sequencing platform. The resultant sequences were aligned to the human reference genome (GRCh38.p13/) via the BWA program [PMID: 20080505, 23155063]. Somatic mutations were delineated utilizing the LoFreq (version 2) variant caller [PMID: 23066108, 19505943], with exclusive consideration given to non-synonymous and splice site variants within coding regions for clinical interpretation. For RNA-level gene fusions, a comprehensive approach involving multiple fusion detection programs was employed. Subsequent mutation annotation transpired through an internally developed pipeline, VariMAT. The VeP program [PMID: 27268795] facilitated gene annotation against the Ensembl release 99 human gene model [PMID: 29155950]. Clinically pertinent mutations were meticulously annotated via peer-reviewed publications, public clinical databases (ClinVar, HGMD, CiViC), and authoritative medical guidelines (NCCN, ASCO, AMP).14 The assay's limit of detection stands at 5% for SNVs and short indels in DNA libraries. Notably, only fusions detected with >10 spanning reads were considered for reporting, aligning with stringent internal validation parameters.
Risk stratification
Initial risk-stratification was based on age (>10 years), TLC count> 50,000/cm as per National Cancer Institute (NCI) and subsequently on response to treatment (Absolute blast count on day-8 of steroids, complete morphological and clinical remission and MRD by FCM at end-induction-1). Cut-off for high-risk D-8 ABC was ≥1000/cm and positive MRD was>0.01% by FCM. Malnourishment was defined as weight for age<−2z score as per the World Health Organization. Bulky disease was defined as lymph node enlargement> 5 cm, hepatomegaly or splenomegaly crossing umbilicus or mediastinum mass > one-third of chest diameter.
Data collection
Demographic, clinical and laboratory characteristics of patients including aberrant myeloid and T-ALL FCM markers were recorded at the time of diagnosis. High-risk ALL features at diagnosis (Age≥10 years, TLC≥50,000/cm, central nervous system (CNS) disease, NCI risk-stratification and bulky disease) and high-risk features subsequent to initial risk stratification (High D-8 ABC and MRD) were compared in two groups: BCR-ABL1-like aberrations positive (Mut+) and BCR-ABL1-like aberrations negative (Mut-). The therapy for ALL was based on Berlin Frankfurt Munster (BFM-2002) protocol as backbone. The enrolled patients were followed up for a minimum period of one year to document short-term outcomes. Survival data recorded as event-free survival (EFS) as end point (death or relapse).
Statistical analysis
All the categorical variables are expressed as numbers and percentages. The comparisons were performed using Fisher exact or Chi-squared test. Median values are compared with Mann–Whitney U test. Survival analysis is represented as Kaplan Meier graph and compared with Log-rank test. A p-value of <0.05 was taken as significant. All data was analysed using SPSS software (version 23.0).
Results
Out of 214 eligible children with B-ALL, a total of 75 children with “B-other ALL” with median age of 54 months (Range: 1–144) were analysed (Fig. 1). The prevalence of Mut+ in our cohort was 34/214 (15.8%) of all children with B-ALL and 34/75 (45.3%) of all analysed “B-other” ALL [PCR-based methodology: 10/30 (33.3%) and NGS-based methodology: 24/45 (53.3%)]. Types of BCR-ABL1-like aberrations are shown in Fig. 2.
Fig. 1.
Flow chart of study participants.
Fig. 2.
Types of genetic aberrations in BCR-ABL1-like ALL in our cohort by PCR (n = 30) and NGS (n = 45).
CRLF2 overexpression was seen in 20/30 (66.6%) cases analysed by PCR. CRLF2 was down-regulated in 7/30 and 3/30 cases had no CRLF2 expression. CRLF2 overexpression was seen in 6/10, while under-expression was seen in 3/10 and no expression in 1/10 of BCR-ABL1-like genetic aberration-positive cases by PCR.
Baseline demographic, clinical, laboratory including aberrant FCM parameters, and risk-stratification groups as per NCI were comparable in Mut+ and Mut-groups (Table 1). Number of cases with D-8 ABC was higher in Mut+ group, while high MRD was comparable in two groups. The number of NCI-standard risk (SR)-ALL at diagnosis with high D-8 ABC or high MRD was higher in Mut+ group. In the final risk-stratification high-risk (HR) ALL was significantly higher in Mut+ group (Table 2). Similar results were found when two groups with and without BCR-ABL1-like aberrations were analysed by NGS alone (Table 3).
Table 1.
Baseline demographic, clinical, laboratory and flowcytometry parameters in two groups at diagnosis.
| Parameter | Total (%) (N = 75) | Mut+ (n = 34) | Mut- (N = 41) | P value |
|---|---|---|---|---|
| Gender | ||||
| Male | 52 (69) | 23 | 29 | 0.77 |
| Female | 23 (31) | 11 | 12 | |
| Age at diagnosis (year) | ||||
| <10 | 69 (92) | 32 | 37 | 0.68 |
| ≥10 | 6 (8) | 2 | 4 | |
| Malnourishment | ||||
| Yes | 19 (25) | 8 | 11 | 0.74 |
| No | 56 (75) | 26 | 30 | |
| Mediastinum mass at diagnosis | ||||
| Yes | 2 (3) | 1 | 1 | 1.0 |
| No | 73 (97) | 33 | 40 | |
| Total leucocyte count at diagnosis (/cm) | ||||
| <50,000 | 51 (68) | 21 | 30 | 0.29 |
| ≥50,000 | 24 (32) | 13 | 11 | |
| Bulky disease at diagnosis | ||||
| Yes | 15 (20) | 7 | 8 | 1.0 |
| No | 60 (80) | 27 | 33 | |
| Aberrant markers on diagnostic flowcytometry | ||||
| Yes | 12 (16) | 4 | 8 | 0.52 |
| No | 63 (84) | 30 | 33 | |
| CSF at diagnosis for blasts | ||||
| Positive | 1 (1) | 0 | 1 | 1.0 |
| Negative | 74 (99) | 34 | 40 | |
| NCI Risk at diagnosis | ||||
| SR | 48 (64) | 21 | 27 | 0.81 |
| HR | 27 (36) | 13 | 14 | |
NCI: National Cancer Institute, SR: Standard Risk, HR: High Risk, CSF: Cerebrospinal Fluid.
Table 2.
Association of BCR-ABL1-like ALL with treatment response and outcome in entire conort.
| Parameter | Total (%) (N = 75) | Mut+ (n = 34) | Mut- (N = 41) | P value |
|---|---|---|---|---|
| Day-8 Absolute blast count (D-8 ABC) | ||||
| High (<1000/cm) | 8 (11) | 7 | 1 | 0.02 |
| Normal (≥1000/cm) | 67 (89) | 27 | 40 | |
| End induction 1 bone marrow remission∗ | ||||
| Yes | 72 (99) | 32 | 40 | 0.45 |
| No | 1 (1) | 1 | 0 | |
| Minimal Residual Disease (MRD) Post Induction∗ | ||||
| Positive | 12 (16) | 8 | 4 | 0.12 |
| Negative | 61(84) | 25 | 36 | |
| NCI SR at diagnosis with high D-8 ABC or high MRDa,∗ | ||||
| Yes | 12 (16) | 9 | 3 | 0.02 |
| No | 61 (84) | 24 | 37 | |
| Final treatment risk | ||||
| Non-HR | 25 (33) | 7 | 18 | 0.03 |
| HR | 50 (67) | 27 | 23 | |
| Outcome | ||||
| Alive | 56 (75) | 25 | 31 | 0.83 |
| Event∗∗ (Death/Relapse) | 19 (25) | 9 | 10 | |
SR: Standard Risk, HR: High Risk.
∗One Induction death each in two groups.
∗∗In Mut+: Induction death-1, Death following relapse-8.
∗∗In Mut-: Induction death-1, Consolidation death-1, Death following relapse-7, Relapse on treatment-1.
Significant p value depicted in bold.
Two children in Mut+ group had both high D-8 ABC and high MRD. None of children in Mut-group had high D-8 ABC.
Table 3.
Association of BCR-ABL1-like ALL with treatment response and outcome when genetic aberrations were analysed by NGS alone.
| Parameter | Total (N = 45) | NGS Mut+ (n = 24) | NGS Mut-(N = 21) | P value |
|---|---|---|---|---|
| Day-8 Absolute blast count (D-8 ABC) | ||||
| High (≥1000/cm) | 7 (16) | 6 | 1 | 0.03 |
| Normal (<1000/cm) | 38 (84) | 18 | 20 | |
| End induction 1 bone marrow remissiona | ||||
| Yes | 43 (98) | 23 | 20 | 1.0 |
| No | 1 (2) | 1 | 0 | |
| Minimal Residual Disease (MRD) Post Induction 1a | ||||
| Positive | 9 (20) | 6 | 3 | 0.4 |
| Negative | 35 (80) | 18 | 17 | |
| NCI SR at diagnosis with high D-8 ABC or high MRDa | ||||
| Yes | 10 (23) | 8 | 2 | 0.03 |
| No | 34 (77) | 16 | 18 | |
| Final treatment risk | ||||
| Non-HR | 11 (24) | 3 | 8 | 0.02 |
| HR | 34 (76) | 21 | 13 | |
| Outcome | ||||
| Alive | 33 (73) | 17 | 16 | 0.16 |
| Event (Death) | 12 (27) | 7 | 5 | |
NGS Mut+: BCR-ABL1-like genetic aberration positive by NGS alone.
NGS Mut-: BCR-ABL1-like genetic aberration negative by NGS alone.
SR: Standard Risk, HR: High Risk.
Significant p value depicted in bold.
One induction death in NGS Mut-group.
Median follow-up of entire cohort was 1075 days (IQR: 660–1527). In all 56 children are alive, 19 had an event (relapse/death). In Mut+ cases, 26% had an event and CIR was 24%. Median survival in Mut+ group was 817 days (IQR: 433–1232) and Mut- group was 1147 days (IQR: 657–1311) (p ≥ 0.05).The outcomes were not significantly different in two groups when analysis was based on combined methodology as well as NGS-based methodology alone (Table 2, Table 3 and Fig. 3).
Fig. 3.
Kaplan Meier survival graph comparing event-free survival in BCR-ABL1-like ALL (Mut+) verses group without genetic aberration (Mut-) [Log-rank p-value = 0.41].
Discussion
BCR-ABL1-like ALL, which was a provisional entity till now, have been included as a newer sub-class of B-ALL as per recent international consensus classification of ALL.15 BCR-ABL1-like ALL represents a biologically and clinically perplexing subclass of ALL mainly due to genomic heterogeneity and non-availability of standardized diagnostic tests. There is considerable overlap in the definition of BCR-ABL1-like signatures in the previously published studies adding to predicament regarding the actual prevalence of this newer sub-class of ALL.6
Prevalence of BCR-ABL1-like mutation was 15.8% of children with B-ALL and 45.3% of “B-other ALL” cases (33% by PCR and 53% by NGS) in our study. The median pooled prevalence in children in recent meta-analysis suggests it to be 15–26% in B-ALL cases and around 50% in “B-Other ALL” cases. The studies included in the meta-analysis spanned over 15 years (1990–2015) with varied methodology.10 One such study from India, in 157 children of B-ALL demonstrated a prevalence of BCR-ABL1-like ALL to be 5.2% and 22% with algorithmic approach and 9% and 38% with addition of targeted RNA-sequencing in entire B-ALL and “B-other ALL” cohort respectively.16 In another study from India the incidence was 34% when analysed by PHi-RACE classifier technique in 108 cases of B-ALL.17 Novel signatures of BCR-ABL1-like ALL are being described with advanced technologies such as NGS, thereby increasing the prevalence.7,8,14
Commonly seen aberrations with PCR were JAK2E16 and ILR7e5/ILR7e6; and RAS pathway (NRAS, KRAS), PAX5 fusion, FLT3-ITD, TP53 and MEF2D:STAT6 with NGS in our cohort (Fig. 2). Most of the aberrations were targetable. The prevalence of individual aberration was different in our cohort compared to existing literature.3,14,18 A high prevalence (68%) of RAS pathway mutations in BCR-ABL1-like ALL was also described recently in children with B-ALL in Korea.19 The exact role of CRLF2 overexpression and its association with BCR-ABL1-like ALL is not clear. Moreover, data on CRLF2 rearranged B-ALL are not exclusively limited to BCR-ABL1-like ALL.7,20 In our study also BCR-ABL1-like aberrations were not seen exclusively with CRLF2 over-expression.
BCR-ABL1-like ALL is associated with high-risk prognostic features like higher age, male sex, high TLC at diagnosis and poor treatment response like high end-induction MRD and increased risk of induction failure and relapse.5,7,10,18 One such study which used BFM-protocol like ours, reported poor early treatment response post induction (71.4%), poor EFS (49.6%), poor OS (69.6%), high CIR (25.6%) and high treatment-related mortality (TRM) (20.8%).21 In our cohort age >10 years, male gender, high TLC, bulky disease at diagnosis were not associated with BCR-ABL1-like ALL. Aberrant FCM markers, as previously reported, were not associated with BCR-ABL1-like ALL in our cohort.17 Limited sample size in our study may explain these anomalies. Early treatment non-response marker like high D-8 ABC was associated; while high end-induction MRD was not associated with BCR-ABL1-like ALL in our study. We upgraded the therapy to high-risk protocol on the basis of high D-8 ABC, which might explain the above inconsistency.
BCR-ABL1-like ALL are less frequent in NCI SR-ALL compared to NCI HR-ALL.22 Initial NCI risk-stratification was comparable in our cohort at diagnosis. But at end-induction, NCI-SR at diagnosis with high D-8 ABC or high MRD suggesting poor initial treatment response was significantly high in the BCR-ABL1-like ALL, suggesting an impact of BCR-ABL1-like signatures on final-risk stratification.
BCR-ABL1-like ALL with poor initial treatment response can be salvaged with risk-directed therapy.23,24 Poor early treatment response at end-induction, CIR and an event (relapse/death) was seen in 26%, 24% and 26% in BCR-ABL1-like ALL in our study. However, the outcomes were comparable to cases without BCR-ABL1-like signatures, highlighting the importance of D-8 ABC- and MRD-based risk-directed therapy to overcome poor outcomes associated with BCR-ABL1-like ALL. Best therapeutic strategy for this sub-group of patients is still investigational, therefore despite targetable aberrations, we did not opt for upfront therapeutic interventions.7,8 However, in relapsed or refractory cases, targeted therapies were tried on case-to-case basis.
Our study had few limitations. It was a single-centrestudy with limited sample size and with a short follow-up period. Due to constraints related to prevailing COVID-19 pandemic, methodology was changed. There was a loss of 25% samples due to inadequate quality/quantity of extracted genetic material. NGS-based whole transcriptome sequencing is a viable approach for detection of all relevant gene fusions and aberrations in one-step, which have helped in early diagnosis and timely application of targeted therapy in BCR-ABL1-like ALL.11,14 It has been strongly recommended to utilize NGS-based strategies especially in “B-other” ALL.7,8 We used NGS-based methodology in majority of our cohort and found results similar to what we found in analysis of entire cohort.
To conclude, we report the prevalence of BCR-ABL1-like ALL in children<14 years as 15.8% of all B-ALL and 45% of “B-other” ALL by PCR- or NGS-based methodology. Majority of BCR-ABL1-like aberrations were JAK2E16 and ILR7e5/ILR7e6 with PCR and RAS pathway (NRAS, KRAS) and PAX 5 fusion with NGS. A high D-8 ABC was associated with BCR-ABL1-like ALL suggesting poor initial treatment response. Outcomes were comparable irrespective of BCR-ABL1-like aberrations, highlighting the importance of D-8 ABC- and MRD-based risk-directed therapy to overcome poor outcomes associated with BCR-ABL1-like ALL. Due to rarity of BCR-ABL1-like ALL, collaborative studies are the need of the hour to further de-lineate clinical, therapeutic and prognostic association of this sub-group of ALL.
Patients/ Guardians/ Participants consent
Patients informed consent was obtained.
Ethical clearance
Institute/hospital ethical clearance certificate was obtained.
Source of support
This paper is based on Armed Forces Medical Research Committee Project No. 5162/2019 granted and funded by the office of Directorate General Armed Forces Medical Services and Defence Research Development Organisation, Government of India.
Disclosure of competing interest
The authors have none to declare.
Acknowledgment
We acknowledge the children with ALL and their parents for bestowing their faith in treating team.
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