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Keywords:

  • acute leukaemia;
  • childhood leukaemia;
  • genetics

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information

The prognostic relevance of CRLF2 -rearrangements in childhood acute B-cell precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis of 114 non-Down-syndrome patients (99 P2RY8-CRLF2+ , 15 IGH@-CRLF2+ ), 76 from the AIEOP-BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6-year cumulative relapse incidence of P2RY8-CRLF2+ patients treated on the two trials was not statistically different: 0·37 ± 0·06 vs. 0·25 ± 0·08 (= 0·194). In contrast, 0/9 IGH@-CRLF2+ AIEOP-BFM, but 5/6 ALL97 patients relapsed. Conclusively, P2RY8-CRLF2+ patients had an intermediate protocol-independent outcome while the different prognosis of IGH@-CRLF2+ patients could be related to the different structures of the applied treatment protocols.

Recently, a group of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients was identified that shared a deregulated expression of the pseudoautosomal cytokine receptor-like factor 2 gene (CRLF2) (Mullighan et al, 2009; Russell et al, 2009). Its overexpression frequently derives from one of two specific genetic lesions. In the majority of cases CRLF2 is fused to the promoter of the P2RY8 gene (CRLF2-P2RY8) or, less commonly, put under the control of the IGH@ enhancer (IGH@-CRLF2).

According to a Children's Oncology Group (COG) report, such rearrangements (particularly IGH@-CRLF2) are more frequent in National Cancer Institute (NCI) high-risk (HR) patients of Latin/Hispanic ethnicity (29/207, 14%) and associated with a poor outcome (Harvey et al, 2010). The COG also showed that, while high CRLF2-expression predicted a dismal outcome, the two specific genomic CRLF2-lesions did not confer independent prognostic significance (Chen et al, 2012). Similarly, CRLF2-rearrangements also had no independent prognostic value in the Medical Research Council (MRC) ALL97 trial. Treatment outcome of CRLF2-rearranged patients was within the same range as of the intermediate cytogenetic risk group (Ensor et al, 2011). On the other hand, the Berlin-Frankfurt-Münster (BFM) and Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) study groups originally screened for patients with high levels of CRLF2-expression and thereby identified P2RY8-CRLF2+ patients in the non-HR group who had a dismal prognosis that was not recognizable by minimal residual disease (MRD) criteria (Cario et al, 2010; Palmi et al, 2012).

As all studies used different diagnostic approaches as well as variable selection criteria for their screening tests, the issue, whether particular arbitrary expression levels or the clearly defined genetic markers are more useful providers of the desired prognostic information remains largely unresolved, at least within the European-based childhood ALL studies.

To further investigate this matter we collected all data from patients with either P2RY8-CRLF2 or IGH@-CRLF2 fusions that were identified in the AIEOP-BFM ALL 2000 (Austria, Germany, Italy) and MRC ALL97 (UK) therapy trials and performed a comparative analysis of their treatment outcome. Notably, this study was not designed to compare the outcome of CRLF2+ and CRLF2– patients among the two therapy trials themself but to assess whether the outcome of CRLF2-rearranged patients is influenced by the composition and intensity of the different treatment regimens.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information

The different selection criteria and diagnostic approaches used by the four study groups [BFM-A (Austria), BFM-G (Germany), AIEOP, MRC] to identify patients with either of the respective CRLF2-rearrangements are shown in Table SI (Cario et al, 2010; Ensor et al, 2011; Palmi et al, 2012). Representative cohorts of patients from the four study groups were screened for genetic alterations using standard techniques as previously described (Cario et al, 2010; Ensor et al, 2011; Palmi et al, 2012). The present study collected individual patient data from three previous analyses: BFM-G (Cario et al, 2010), MRC (Ensor et al, 2011) and AIEOP (Palmi et al, 2012). All patients included were positive for either P2RY8-CRLF2 or IGH@-CRLF2; patients with CRLF2-overexpression alone or Down-syndrome were excluded.

Treatment stratification and protocols were published previously (Mitchell et al, 2005; Vora et al, 2006; Conter et al, 2010). Patients were treated with informed consent from the patients, their parents or legal guardians. Studies were conducted in accordance with the Declaration of Helsinki and approved by the relevant ethic committee. Event-free (EFS) and overall (OS) survival rates were analysed according to the Kaplan–Meier method and compared by the log-rank test. Cumulative incidence of relapse (CIR) was constructed by the Kalbfleish and Prentice method and compared with the Gray test. Multivariate analysis was performed using the Cox proportional hazards model.

Results and discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information

A total of 114 CRLF2-rearranged cases was identified, constituting the largest compilation of such patients to date, and comprised 22 cases from BFM-A, 20 from BFM-G, 34 from AIEOP and 38 from MRC ALL97. A total of 99 (87%) had P2RY8-CRLF2 and 15 (13%) IGH@-CRLF2 fusions. Table 1 summarizes the clinical, laboratory and outcome data of the 76 AIEOP-BFM (67 P2RY8-CRLF2+ and nine IGH@-CRLF2+) and the 38 MRC ALL97 patients (32 P2RY8-CRLF2+ and six IGH@-CRLF2+). The distribution of additional genetic aberrations was similar in both cohorts (Table SII). To enable comparison with the COG studies, we also evaluated P2RY8-CRLF2+ and IGH@-CRLF2+ patients with respect to the NCI standard-risk (SR) and HR criteria. Although there was a similar trend, with more IGH@-CRLF2+ patients seen in the NCI HR group (9/46 NCI HR and 6/68 NCI SR patients), the less pronounced frequency may be due to the facts that: (i) not all our original patients were analysed for IGH@-CRLF2, (ii) ALL97 mostly recruited NCI SR patients and (iii) COG studies generally enroll more Latin/Hispanic cases, in which this aberration is particularly prevalent (Chen et al, 2012).

Table 1. Clinical, laboratory and outcome features of 114 CRLF2 -rearranged B-cell precursor ALL patients treated on the AIEOP-BFM ALL 2000 and MRC ALL97 trials
AIEOP-BFM ALL 2000MRC ALL97 P-value
  1. MRD, minimal residual disease; CNS, central nervous system; NS, not significant; NCI, National Cancer Institute.

  2. a

    Toxic death in induction therapy.

  3. b

    MRC ALL97 trial: period 1997–99: recruited standard-risk patients only (= 13); period 1999–2003: recruited patients from all three risk groups (= 25); AIEOP-BFM ALL 2000 trial: recruited patients from all three risk groups (= 76).

  4. c

    31/41 (76%) MRD-negative after induction consolidation (at TP2).

  5. d

    14/20 (70%) MRD-negative after induction consolidation (at TP2).

  6. e

    Cause of death unknown for one patient.

CRLF2-rearranged patients (N)7638
Initial disease
 Sex
Male37 (49%)15 (39%)
Female39 (51%)23 (61%)NS
 Age (years)
Median5·304·96 
Range1·23–15·981·45–12·21 
<10 years56 (74%)35 (92%) 
≥10 years20 (26%)3 (8%)0·02
 White cell count (×109/l)
Median15·8021·90
Range0·9–379·01·0–649·0
<50·0 × 109/l58 (76%)28 (74%)
≥50·0 × 109/l18 (24%)10 (26%)NS
CNS disease2 (3%)0NS
 CRLF2 –rearrangement
P2RY8-CRLF2 67 (88%)32 (84%) 
IGH@-CRLF2 9 (12%)6 (16%)NS
 Prednisone response
Good73 (96%) 
Poor3 (4%)
Complete remission75 (99%)a 38 (100%)NS
 Final risk groupb
Standard-risk22 (29%)30 (79%)<0·0001
Intermediate-risk47 (62%)3 (8%)
High-risk 5 (6·5%)5 (13%)
Death before stratification2 (2·5%)0
 MRD risk group
Low-risk25 (33%) 
Intermediate-risk41 (54%)c  
High-risk2 (3%) 
Not available 8 (10%)38 (100%)
 NCI risk group
Standard-risk43 (57%)25 (66%)
High-risk33 (43%)13 (34%)NS
Relapse24 (32%)13 (34%)NS
 Site
Bone marrow157 
CNS33 
Bone marrow + CNS31 
Other32 
Median time to relapse (years)2·83·3 
Range0·4–4·51·7–9·9
 CRLF2-rearrangement
P2RY8-CRLF2 24 (100%)8 (62%) 
IGH@-CRLF2 05 (38%) 
 Initial final risk group
 Non-high-risk group24 (100%)12 (92%) 
 High risk group01 (8%) 
 Initial MRD risk group
Low-risk3 (13%) 
Intermediate-risk20 (83%)d  
High-risk0 
Not available1 (4%) 
 Initial NCI risk group
Standard-risk15 (63%)9 (69%)
High-risk9 (37%)4 (31%)
Outcome
 Secondary malignancy1 (1%)0NS
 Death13 (17%)12 (32%)e NS
Relapse74
Toxicity67
 Follow-up (years)
Median7·95·8 
Range3·5–11·91·2–10·1 

The vast majority of AIEOP-BFM patients (73/76, 96%) were good prednisone responders. MRD results were available in 68/76 patients. Three of the 25 patients that were assigned to the MRD low-risk (LR) group (37%) relapsed. Only two cases (3%) fulfilled MRD HR criteria. The remaining 41 patients (60%) were stratified to the MRD intermediate-risk (IR) group and included 31 (76%) who were MRD-negative at time-point 2 (TP2). The vast majority of AIEOP-BFM patients who relapsed belonged to the MRD-IR group (20/23, 87%) with 14/20 (70%) MRD-negative at TP2.

With a median follow-up of 5·6 years for the AIEOP-BFM and 7·5 years for the ALL97 trial, 6-year EFS rates of P2RY8-CRLF2+ patients were 59 ± 6% and 72 ± 8% respectively (P = 0·127; Fig 1A). The 6-year CIR (0·37 ± 0·06, 0·25 ± 0·08; = 0·194) was not statistically different and, importantly, the 6-year OS (83 ± 5%, 81 ± 7%; P = 0·936) was identical in both studies (Fig 1B, C). The 6-year EFS, CIR and OS for the 37 P2RY8-CRLF2+ patients in the AIEOP-BFM MRD-IR group were 45 ± 8%, 0·55 ± 0·08% and 77 ± 7% respectively (Fig 1D). The majority of AIEOP-BFM patients who relapsed are alive in second CR (15/24, 62%) with a median follow-up of 2·4 years, whereas 6/8 (75%) ALL97 patients who experienced a relapse died. Of note, all nine IGH@-CRLF2+ AIEOP-BFM patients remained in first CR, whereas in the ALL97 patient cohort 5/6 relapsed and died.

image

Figure 1. (A) Six-year event-free survival (EFS), (B) cumulative incidence of relapses (CIR), (C) overall survival (OS) of the 67 P2RY8-CRLF2+ patients from trial AIEOP-BFM ALL 2000 as compared with the 32 P2RY8-CRLF2+ patients from trial MRC ALL97 and (D) cumulative incidence of relapses (CIR) of the 37 P2RY8-CRLF2+ and 4 IGH@-CRLF2+ minimal residual disease, intermediate risk (MRD-IR) AIEOP-BFM ALL 2000 patients.

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In the AIEOP-BFM trial, MRD risk stratification and the type of CRLF2-rearrangement were the only parameters that predicted relapse (P = 0·002; P = 0·043). Only type of CRLF2-rearrangement (P = 0·022) was prognostic for the ALL97 patients. In multivariate analysis, the type of CRLF2-rearrangement retained its significance in the AIEOP-BFM but not in the ALL97 patient cohort (Table SIII).

In the ALL97 trial CRLF2-rearrangements did not emerge as independent risk factors, whereas screening for primarily CRLF2-overexpression in the German and Italian AIEOP-BFM ALL study apparently identified P2RY8-CRLF2 as a HR-feature (Cario et al, 2010; Ensor et al, 2011; Palmi et al, 2012). Our extended analysis of P2RY8-CRLF2+ and IGH@-CRLF2+ patients now provides good evidence that the EFS and OS as well as the CIR of P2RY8-CRLF2+ patients were not statistically different between the AIEOP-BFM and ALL97 trials. Thus, P2RY8-CRLF2+ patients have a moderate or intermediate prognosis with EFS rates at 60–75%, confirming that these patients are treated with comparable efficiency in both studies (Mitchell et al, 2005; Conter et al, 2010). Although the prognostic effect of high CRLF2-expression per se has not been taken into consideration in the present study, recent reports from the AIEOP-BFM study group have shown that high CRLF2-expression does not confer independent prognostic significance among patients with BCP-ALL (Cario et al, 2010; Palmi et al, 2012). In comparison, the COG showed that, when stratifying the patients by NCI criteria, high CRLF2-expression was associated with a poor prognosis (c. 40–50% relapse-free survival) among NCI HR patients. In addition, among this group of patients, cases with and without a CRLF2-rearrangement did equally poorly (Chen et al, 2012).

In the AIEOP-BFM study, P2RY8-CRLF2+ patients had an excellent outlook if they become MRD-negative after induction therapy. Thus, the current chemotherapy regimens seem to be sufficient for this subgroup. P2RY8-CRLF2+ patients in the MRD-IR group still have a slightly higher relapse risk than expected, a fact that at least warrants their close monitoring in the future. Given that two-thirds of the AIEOP-BFM relapse patients are surviving event-free after contemporary relapse treatment (though longer follow-up is needed to see the actual cure rates), the immediate therapy of all P2RY8-CRLF2+ MRD-IR patients with a HR-protocol seems inappropriate, especially when one considers the risk of early treatment-related morbidity and mortality. Notably, only one of four AIEOP-BFM and one of four ALL97 patients in the HR-group relapsed.

Our most perplexing finding was the pronounced difference in the treatment outcome of IGH@-CRLF2+ patients, in which all nine AIEOP-BFM patients remained in first CR, while 5/6 ALL97 patients relapsed and died. Whilst this could be simply due to small numbers of cases, differences in the treatment protocols could also be a factor, such as the earlier intensification in the AIEOP-BFM protocol (four-drug induction, induction consolidation, interval therapy with high-dose methotrexate and single delayed induction therapy for all non-HR patients) compared to the later intensity in the ALL97 study (three-drug induction, no induction consolidation, no high-dose methotrexate in interval therapy but two double delayed induction protocols for all SR patients) (Mitchell et al, 2005; Conter et al, 2010). Alternatively or, in addition, other associated biological and genetic risks, such as IKZF1 deletions, must be taken into consideration as contributing factors (Ensor et al, 2011; Chen et al, 2012). Intriguingly, the COG did not find a difference in outcome according to the type of the CRLF2-rearrangement. Whether the equally poor prognosis of IGH@-CRLF2 among their patient cohort is due to its association with other poor prognostic parameters, such as Latin/Hispanic ethnicity or NCI HR criteria, remains to be determined (Harvey et al, 2010; Chen et al, 2012).

We conclude that although a final verdict on the clinical relevance of P2RY8-CRLF2 and IGH@-CRLF2 fusions in childhood BCP-ALL is not yet possible, we believe that there is currently no immediate necessity for enrolling all P2RY8-CRLF2+ patients into the HR-arm of ongoing cooperative multicentre ALL trials. Nevertheless, the potential clinical and biological relevance of CRLF2-rearrangments remains of interest and requires close scrutiny in the future (Harvey et al, 2010; Chen et al, 2012).

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information

We thank all participating institutions and physicians for their support of the study. BFM-Austria was supported in part by grants from the Austrian National Bank (ÖNB 14129 to M. M.) and a clinical investigator-driven (CID) grant from the “St. Anna Kinderkrebsforschung” to A. A., O. A. H., G. M. and R. P-G., BFM-Germany was supported by the “Deutsche Krebshilfe”, the Kinderkrebsinitiative Buchholz/Holm-Seppensen, and the Madleine-Schickedanz-Kinderkrebsstiftung, and AIEOP was supported by the AIL, Associazione Italiana Contro le Leucemie, Fondazione Cariplo and Fondazione Citta della Speranza, MIUR, and Associazione Italiana per la Ricerca sul Cancro. A. V. M. and C. J. H. would like to thank Leukaemia and Lymphoma Research of the UK for financial support, the UK Cancer Cytogenetics Group (UKCCG) for providing cytogenetic data and material, and the clinical trial management team of the ALL97/99 study.

Author contributions

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information

A. A., G. C., G. C., T. K., M. St., C. J. H., R. P.-G., and A. V. M. designed the study and supervised the project; A. A., O. A. H., G. C., G. C., and A. M. wrote the manuscript with contributions from S. S. and R. P.-G.; A. M., M. Z., U. P. and H. E. were in charge of data pooling, data checking and statistical analysis; A. A. also performed statistical analysis; M. M., C. S., L. R., T. K., J. H., E. V., C. P. and S. S. performed the molecular-genetic analyses; A. A., G. C., G. C., H. E., O. A. H., M. St., R. P.-G., and A. V. M. interpreted the data; A. A., M. M., G. M., M. S., V. C., and C. M. were principal or co-investigators in their study groups, coordinated the study in their countries and recruited patients. All authors read and approved the final version of the manuscript.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results and discussion
  5. Acknowledgements
  6. Author contributions
  7. Conflict of interest and disclosure
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
bjh9221-sup-0001-TableS1.docWord document38K Table SI. Selection criteria (period, number of patients) and method of screening for 114 CRLF2 -rearranged non-Down-syndrome B-cell precursor ALL patients treated in the AIEOP-BFM ALL 2000 and MRC ALL97 trials.
bjh9221-sup-0002-TableS2-S3.docWord document50K Table SII. Cytogenetic and molecular-genetic classification of 114 CRLF2 -rearranged B-cell precursor ALL patients treated in the AIEOP-BFM ALL 2000 and MRC ALL97 trials. Table SIII. Multivariate risk factor analysis* for relapse risk of the AIEOP-BFM ALL 2000 patients including the 66 MRD low-risk and intermediate-risk patients only.

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