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Keywords:

  • Philadelphia chromosome;
  • acute lymphoblastic leukaemia;
  • childhood;
  • clinical trials

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

We report on the outcome of children with Philadelphia positive acute lymphoblastic leukaemia (Ph+ ALL) treated on the UK Medical Research Council (MRC) trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Forty-two (2·3%) patients were Ph+. Nineteen (45%) had <25% blasts in bone marrow (BM) within the first 2 weeks of treatment and were defined as a good response group (GRG), the others as a poor response group (PRG). Thirty-six (86%) achieved first complete remission (CR1) at the end of induction, of which 28 underwent BM transplantation (BMT). The median follow-up was 42 months (range, 21–84). The 3-year event-free survival (EFS; 52%, 95% CI, 36–66%) was a considerable improvement on the previous MRC UKALL XI trial (27%). EFS for the GRG and PRG were 68% (43–84%) and 39% (18–59%), respectively (P = 0·03); presenting white cell count <50 × 109/l (P = 0·02) was predictive for overall survival. Changes in the MRC ALL97 trial within the study period resulted in some Ph+ ALL receiving daunorubicin and either prednisolone or dexamethasone during induction. Though the use of daunorubicin during induction was not a prospective study question, EFS was significantly better for those whose induction included this drug (P = 0·02). Steroid randomization was not stratified for Ph+ ALL patients and was not predictive for EFS. BMT in CR1 appeared to reduce the risk of a subsequent BM relapse. These results show significant improvement on previous MRC trials; future therapeutic strategies should include early intensive therapy and BMT in CR1.

Many of the cytogenetic subtypes of childhood acute lymphoblastic leukaemia (ALL) are associated with a poorer outcome (Pui et al, 1990). In particular, the Medical Research Council (MRC) UKALL XI trial found that those with near haploidy, a t(4;11)(q21;q23) or a t(9;22)(q34;q11) had significantly worse prognosis (Hann et al, 2001a). UKALL XI did not risk stratify children for treatment and the 5-year survival for those with Philadelphia chromosome positive (Ph+) ALL was 27% (Hann et al, 2001a).

The Berlin-Frankfürt-Münster – Associazione Italiana Ematologia Oncologia Pediatrica (BFM-AIEOP) group, in two consecutive trials spanning 1986–95, treated children with Ph+ ALL with intensified protocols and reported a 4-year overall survival (OS) of 49%. They also found that the response to treatment, as defined by the number of circulating blasts after a week of prednisolone and a single dose of age-adapted intrathecal methotrexate, to be the only other independent prognostic factor in this group (Schrappe et al, 1998). Children with a peripheral blast count of <1 × 109/l at that time point had a 4-year event-free survival (EFS) of 52% while those with a higher count had EFS of 10%. A subsequent meta-analyses of the results obtained by 10 different groups for children with Ph+ ALL concluded that age and presenting white cell count (WCC) were significant predictors for survival and transplantation of marrow from a human leucocyte antigen (HLA)-matched related donor offered a significantly better outcome (Arico et al, 2000). The AIEOP group used a similar strategy for children with Ph+ ALL in the AIEOP ALL-95 trial, which ran from 1995–99. While survival improved in the other high risk groups treated on this protocol, the OS of 51% in those with Ph+ ALL was not significantly better than obtained previously (Arico et al, 2002). As previously observed in the meta-analysis (Arico et al, 2000) and in AIEOP ALL 95, a major factor was the failure to achieve remission in a significant proportion of Ph+ ALL patients. In 1997, the MRC began stratifying children with ALL and treating Ph+ ALL with a more intensified protocol. In this report, we provide the details of treatment and outcome of children with Ph+ ALL treated in the UK from 1997 to 2002.

Patients and diagnosis

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

During the period between January 1997 and June 2002, all untreated patients between 1 and 18 years of age, newly diagnosed with B-precursor or T-cell ALL in the UK were eligible to be treated according to the MRC ALL 97 trial (Hann et al, 2000). The diagnosis of ALL was based on morphological and immunological criteria as defined by the French–American–British working group. A diagnosis of Philadelphia chromosome/t(9;22)(q34;q11)/BCR-ABL positive ALL (Ph+ ALL) was made using standard G-banding cytogenetic and/or fluorescent in situ hybridization (FISH) analysis. FISH analysis was performed using at least one of the following LSI® probes: dual colour single fusion, dual colour extra signal or dual colour dual fusion BCR-ABL translocation probes (Vysis, London, UK). These tests were performed either at the local cytogenetic laboratory and/or centrally by the Leukaemia Research Fund UK Cancer Cytogenetics Group Karyotype Database in Acute Leukaemia (Harrison et al, 2001) based at the University of Southampton.

Treatment

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

During the period of the study, the MRC ALL97 protocol was modified twice. The initial protocol used a three-drug induction (vincristine, steroid and l-asparaginase). Children with Ph+ ALL were treated on a high risk arm (HR1) with a BFM-type re-induction block in between two intensification blocks as described for the MRC UKALL XI protocol (Hann et al, 2001b). There were two randomizations, prednisolone or dexamethasone as the steroid of choice for the entire protocol, and mercaptopurine or thioguanine as the thiopurine of choice for maintenance, but with prednisolone and mercaptopurine for HR1. In the modification introduced in 1999 (ALL97/99), children with adverse cytogenetic features (Ph+ ALL, near-haploidy and those younger than 2 years with a MLL gene rearrangement) or with a slow early response to treatment (Nachman et al, 1997) received a four-drug induction and augmented postinduction therapy as described previously (Nachman et al, 1998). The steroid and thiopurine randomizations were continued into ALL97/99 and E. coli asparaginase (ElsparTM; Merck, Whitehouse Station, NJ, USA) replaced the use of Erwinia Asparaginase in the entire protocol in April 2001. In June 2002, all randomizations were stopped and subsequent patients were treated with dexamethasone and mercaptopurine. All children with Ph+ ALL were eligible to have a bone marrow transplant (BMT) in first complete remission (CR1) with either a matched related (MRD) or matched unrelated (MUD) donor.

Analytical groups

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

For purposes of these analyses, Ph+ ALL children have been grouped into categories according to therapeutic response. Good response patients were those with <25% blasts in the marrow at their first assessment, which was day 8 or 15 for those with a four-drug or three-drug induction respectively. All marrow responses were centrally reviewed as previously reported (Lilleyman et al, 1997). In the good response group (GRG), those aged <10 years and with a presenting WCC of <50 × 109/l were considered as ‘standard-risk’ (SR) while children who did not meet this criteria were classified as ‘intermediate-risk’ (IR). Children in the poor response group (PRG) were those who had ≥25% blasts in the marrow at their first assessment.

Statistical analysis

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

Overall survival was defined as the time from commencement of initial therapy to death from any cause. EFS was calculated as the interval from the date of first therapy to the date of first event. An event was defined as any of the following: resistance to induction/consolidation, relapse and death from any cause. Failure to achieve remission (early death, progression and resistant leukaemia) was assigned a time of 1 day. Where there was no reported event, the patient was assumed to be censored at 31 January 2004. Survival curves and probabilities were computed using the Kaplan–Meier method (Kaplan & Meier, 1958), with 95% Greenwood confidence intervals (CI) given. Descriptive statistics alone are given for those who received transplant or not in CR1. All children were eligible to have a transplant in CR1. A statistical comparison of those who did versus those that did not would be hard to interpret as it would not be an intention to treat analysis. As the use of daunorubicin depended on risk group, the effect of this was assessed by stratified logrank test (Peto et al, 1977), using the risk group as the strata. The randomized treatment comparison (prednisolone vs. dexamethasone), along with other potential prognostic factors, were assessed using a standard logrank test (Peto et al, 1977). As there were several changes in protocol during the trial period and the numbers in each category were limited, multivariate analysis on the outcome was not performed.

Identification of Ph+ ALL patients

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

During the period of the study, 1937 patients with childhood ALL were registered for the ALL 97 trial. A total of 1837 (95%) patients were screened for the t(9;22)/BCR-ABL by G-banding cytogenetic (n = 1600) and/or FISH analysis (n = 1628). Forty-two (2·3%) patients had a t(9;22) and/or BCR-ABL fusion. Twenty-nine of these cases were positive by G-banding and FISH, whereas eight cases were identified by FISH only and five by G-banding only. Five of the eight cases detected by FISH alone were confirmed by reverse transcription polymerase chain reaction (PCR) or a second FISH assay using a different probe. This subgroup of Ph+ ALL patients was heterogeneous at the cytogenetic level with 27 (77%) out of 35 assessable cases having one or more abnormality in addition to the Ph translocation (Table I). Four recurrent secondary abnormalities were observed: an extra Ph chromosome (+Ph) [+der(22)t(9;22)] (n = 12), loss of 9p (del 9p) (n = 10), high hyperdiploidy (51–65 chromosomes) (n = 4) and monosomy 7 (n = 3). All four high hyperdiploidy cases also had an extra Ph chromosome.

Table I.  Details of Ph+ ALL patients treated on MRC ALL 97.
Response groupsAge (years)GenderPresenting WCC × 109/lMajor additional cytogenetic aberrationsTreatment protocolNo. of drugs in inductionInduction steroidRemission statusType of BMT in CR1/PRRelapse type, time (months)Outcome, time (months)BMT in CR2
  1. Patients are listed according to response groups. Good response represents those whose first marrow assessment during induction showed a blast count of <25%; Poor response represents those whose first marrow assessment during induction showed a blast count of ≥25%; Indeterminate represents marrow response unknown. Treatment protocol refers to the version of MRC ALL 97 used. 97 is the original protocol, 99 is the modified versions (see text). Remission status reflects the marrow report at the end of induction.

  2. WCC, white cell count; BMT, bone marrow transplantation; CR1, first complete remission; PR, partial remission; CR2, second complete remission; SR, Standard risk (age < 10 years and presenting WCC < 50 × 109/l); F, female; P, prednisolone; CR, morphological remission obtained at the end of induction; MUD, matched unrelated donor; DpBMT, died post-BMT; M, male; MRD, matched related donor; BM, bone marrow relapse; D, dexamethasone; IR, intermediate risk (age ≥ 10 years or presenting WCC ≥ 50 × 109/l); +Ph, extra Ph chromosome; Del, deletion; HH, high hyperdiploidy; CNS/abdo, relapse in the central nervous system and abdominal nodes; DOD, died of disease; LR, late remission: not in morphological remission at the end of induction but achieved subsequently; NR, morphological remission not achieved by census date; PR, not in morphological remission at the end of induction but partial remission achieved prior to BMT; Auto, autologous rescue, +, months after diagnosis.

Good response
SR
11·8F1·5 993PCRMUD + 12 DpBMT + 19 
21·9M2·2 994PCRMRD + 10 CR1 + 49 
35·2F2·6 994PCRMUD + 6 CR1 + 36 
42·6M6·3 973PCR BM + 43CR2 + 68MUD + 47
52·3M6·7Monosomy 7973DCRMUD + 10 CR1 + 54 
64·6M8 994DCRUnknown donortype + 11 CR1 + 36 
71·3F15·9 973DCR  CR1 + 67 
83·1F19·3 993DCRMRD + 9 DpBMT + 10 
95·7M40 973PCR  CR1 + 82 
IR
1014·7M4·6+Ph994DCRMUD + 7 CR1 + 34 
1115·6M4·7+Ph994DCRMUD + 6 CR1 + 34 
1214·5F12·8Del 9p; HH, +Ph994PCR  CR1 + 46 
1310·6F15·3Monosomy 7973PCRMRD + 13 CR1 + 55 
1411·1M30 973PCR BM + 8CR2 + 61MRD + 14
1515·5M52·8HH, +Ph973PCRMRD + 6 DpBMT + 8 
164·8M61Del 9p973DCRMUD + 5CNS/abdo + 22DOD + 24 
171F108+Ph994DCRMRD + 6 CR1 + 41 
1815·3M200HH, +Ph994PCRMUD + 8 CR1 + 31 
199·2M319·1 994DCRMUD + 8BM + 10DpBMT + 14 
Poor response
2015·9F4Del 9p, monosomy 7994DCRMUD + 6BM + 21CR2 + 37 
212·5F10·2+Ph994PCRMRD + 5 CR1 + 42 
229·9M11+Ph973DCR BM + 51CR2 + 55 
233·4M14HH, +Ph994DCRMUD + 6 CR1 + 25 
246·7F27·3 973DCR BM + 22DpBMT + 32MUD + 28
251·6M29 973DCRMUD + 13 DpBMT + 15 
261·9M57 994PCRMUD + 11 CR1 + 30 
2714·5M143 994DCR BM + 3DpBMT + 10MUD + 5
285·1M167 994PCRMRD + 4BM + 10DpBMT + 18 
295·3M241Del 9p994PCRMUD + 4 CR1 + 37 
3016·2F243 973PCR BM + 1DpBMT + 4MUD + 3
3110·5M262 994PCRMUD + 6 CR1 + 29 
324·3F275Del 9p994PCRMUD + 6 CR1 + 20 
336·9M282 994DCRMRD + 4BM + 9DOD + 21 
3414·7F297Del 9p994PCRMRD + 4BM + 15DOD + 25 
3512·6F20Del 9p, +Ph994PLRMRD + 5 DpBMT + 7 
368·5M113 973PLR BM + 3DpBMT + 9MUD + 6
371·9F339Del 9p994PLRMRD + 6 CR1 + 47 
3811·6F533Del 9p994PNRMUD + 4 (in PR) DpBMT + 12 
394·9M500Del 9p973PNR  DOD + 9 
Indeterminate
408·8M48·5 973PCRMUD + 5 CR1 + 84 
419·1M35+Ph994PCR  Died + 1 
4213·1F27·3+Ph973PLR BM + 18DpBMT + 25Auto + 22

The median age of all Ph+ patients was 6·8 years (range 1·0–16·2 years); there were 25 males and 17 females and the median presenting WCC was 32·5 × 109/l (range 1·5–533 × 109/l). The immunophenotype for all 42 patients was consistent with pre-B or common ALL. The median follow-up among patients still alive at the end of the study period was 42 months (range 21–84 months).

Response to treatment

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

As shown in Table I, 20 (48%) children were classified as PRG. In the GRG, nine were classified as SR and 10 as IR. For three children, a day 8/15 marrow response was not available and these have been categorized as indeterminate. A three-drug induction was used for six (67%) SR, four (40%) IR and six (30%) PRG patients. These were either children who were treated on the original ALL 97 protocol or those in whom a diagnosis of Ph+ ALL was established postinduction.

In the SR group, six received an allogeneic BMT in CR1; three were treated with chemotherapy alone, of whom one relapsed and was transplanted in second complete remission (CR2). There were two deaths in this group; one was transplant-related and the other was caused by infection. In the IR group, eight received an allogeneic BMT in CR1; two were treated with chemotherapy alone, of whom one relapsed and was transplanted in CR2. There were three deaths in this group, two of disease recurrence and one child died of transplant-related problems. In the PRG, one child was a primary non-responder; 13 received an allogeneic BMT in CR1 and one was transplanted in partial remission. five were treated with chemotherapy alone, all of whom relapsed. Of these, four were transplanted in CR2 and one is awaiting a transplant. There were 11 deaths in the PRG. The primary non-responder died 9 months after diagnosis. All four children transplanted in CR2 died of post-transplant complications, as did the child who was transplanted in partial remission. In the 13 children transplanted in CR1, there were two transplant-related deaths and three children died of recurrence of disease. Of the three children in the indeterminate category, one achieved CR but died of infection; one child received an autologous transplant in CR2 but died of post-transplant complications and the other remains in CR1 after a BMT.

Outcome according to risk groups

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

For the group as a whole, the 3-year OS and EFS were 56% (95% CI 39–70%) and 52% (36–66%) respectively (Fig. 1). Table II summarizes the outcome according to the different categories. As shown in Table II and Fig. 2, those with a presenting WCC <50 × 109/l had an OS of 70% (48–85%) and an EFS of 63% (40–78%) compared with an OS of 37% (16–59%) and an EFS of 38% (17–60%) for those with a higher presenting WCC (P = 0·02 for OS and 0·07 for EFS). As shown in Fig. 3, the estimates for 3-year OS & EFS for the GRG were 74% (48–88%) and 68% (43–84%), and for the PRG were 40% (18–62%) and 39% (18–59%) (P = 0·06 for OS and 0·03 for EFS). Thus, children with Ph+ ALL who had an early response to induction therapy had a significantly better outcome. Gender and age at diagnosis were not predictive for outcome.

image

Figure 1. (A and B) Overall survival and event free survival of children with Ph+ ALL treated on the MRC ALL97 trial.

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Table II.  Outcome of Ph+ ALL patients on MRC ALL 97 according to response groups, presenting WCC, age, gender, type of BMT and induction therapy.
 nMedian age (years)Males (%)Median presenting WCC × 109/l (range)3-year OS (95% CI)P3-year EFS (95% CI)P
  1. Abbreviations are defined in Table I.

  2. *Denotes the P value for differences in OS and EFS for the good response and poor response groups.

Overall426·825 (60)32·5 (1·5–533)56 (39–70) 52 (36–66) 
Response groups0·06* 0·03*
 Good response195·212 (63)15·3 (1·5–319)74 (48–88) 68 (43–84) 
  SR92·65 (56)6·7 (1·5–40)78 (36–94) 78 (36–94) 
  IR1012·87 (70)41·4 (4·6–319)70 (33–89) 60 (25–83) 
 Poor response206·811 (55)155·0 (4·0–533)40 (18–62) 39 (18–59) 
 Indeterminate39·12 (67)35·0 (27·3–48·5)    
Presenting WCC0·02 0·07
 <50 × 109/l246·213 (54)70 (48–85) 63 (40–78) 
 ≥50 × 109/l187·712 (67)37 (16–59) 38 (17–60) 
Age at diagnosis0·6 0·28
 <10 years2718 (67)35·0 (1·5–500)58 (37–74) 59 (38–75) 
 ≥10 years157 (47)30·0 (4·0–533)53 (26–74) 40 (16–63) 
Gender0·77 0·99
 Male256·948·5 (2·2–500)60 (38–76) 56 (35–73) 
 Female176·720·0 (1·5–533)51 (26–72) 46 (21–67) 
Donor type BMT0·1 0·1
 MRD in CR1115·14 (36)52·8 (2·2–339)45 (17–71) 45 (17–71) 
 MUD in CR1165·212 (75)38·8 (1·5–319)74 (45–89) 68 (39–85) 
Drugs0·87 0·93
 Prednisolone268·714 (54)50·7 (1·5–533)57 (36–74) 54 (33–71) 
 Dexamethasone165·711 (69)17·6 (4·0–319)55 (27–75) 50 (25–71) 
image

Figure 2. (A and B) Differences in overall survival (OS) and event free survival (EFS) in Ph+ ALL treated on MRC ALL 97 according to presenting white cell count (WCC). The solid line represents EFS and OS in those with a presenting WCC of <50 × 109/l and the dashed line those with a presenting WCC of ≥50 × 109/l.

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image

Figure 3. (A and B) Difference in survival in Ph+ ALL treated on MRC ALL 97 according to early response to therapy. The solid line represents EFS and OS for the GRG and the dashed line for the PRG.

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Outcome according to induction therapy

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

As mentioned in the treatment schedule, children in the MRC ALL 97 trial did not receive anthracyclines (daunorubicin) during induction chemotherapy in the first 2 years of the trial. Subsequently in ALL97/99 those in the IR and high-risk (HR) groups received weekly daunorubicin as part of a four-drug induction. All Ph+ ALL patients entered into ALL 97/99 were eligible to be treated on the high-risk arm. During this period, the diagnosis of Ph+ ALL was made postinduction for two SR patients, who were therefore induced on the standard risk arm with three drugs. Consequently, nine of the 19 GRG (47%) and 14 of the 20 PRG (70%) received daunorubicin during induction. Having adjusted for risk group, patients who received daunorubicin (OS = 86% and EFS = 84%) fared significantly better than those who did not (OS = 61% and EFS 55%), both in terms of OS (P = 0·03) and EFS (P = 0·02).

As a result of the steroid randomization, prednisolone was given to 26 patients (five SR, five IR, 13 HR and all three unknowns) and dexamethasone to 16 (four SR, five IR and seven HR). There was no statistically significant difference according to steroid group in either OS (3-year prednisolone survival 57%, dexamethasone 55%, P = 0·87) or EFS (3-year prednisolone survival 54% and dexamethasone 50%, P = 0·93), but prednisolone was used postinduction in all patients on HR1.

Outcome according to adverse cytogenetic features

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

Of the twelve patients who had an extra Ph chromosome, six were in the GRG, four in the PRG and two in the indeterminate group. Thus six of 10 (60%) of those with an assessable response had a good early response to treatment. Of the 12 patients with an extra Ph chromosome, five experienced an adverse event (two relapses and three deaths) and the remaining seven (58%) are in CR1. Ten patients had a loss of 9p (del 9p). Eight of 10 (80%) belonged to the PRG and two of 10 to the GRG. Of the 10 patients with del 9p, six experienced an adverse event (three relapses and three deaths) and the remaining four (40%) are in CR1.

Postremission treatment

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

In the MRC ALL 97 trial, allogeneic BMT in first remission was recommended for children with Ph+ ALL. Whether a child with Ph+ ALL underwent BMT in CR1 depended on a number of factors, including donor availability. Thus 28 (70%) of the 40 eligible for BMT in CR1 actually underwent the procedure.

As shown in Table I, in the GRG, 14 were transplanted in CR1 of whom nine are alive. Of the five who continued on chemotherapy, two relapses were salvaged with a BMT in CR2, and three have not been transplanted; all five are still alive. In the PRG, 13 were transplanted in CR1, and eight are alive. Of the remaining seven patients, four were transplanted in CR2 and one in partial remission, none of whom are alive. The 3-year EFS for those transplanted in CR1 was 60% and for those who did not undergo BMT in CR1 it was 36%.

As five of the 10 deaths that occurred in those transplanted in CR1 were therapy-related, another way to look at these data is to examine the relapse rate. As derived from Table I, in the GRG patients, there were two (14%) relapses among the 14 transplanted in CR1 whereas two (40%) of the five treated with chemotherapy relapsed. In the PRG, there were four (29%) relapses among the 14 children with a BMT in CR1/PR whereas five (83%) of the six children treated with chemotherapy relapsed. All children were eligible to have a transplant in CR1. However as can be seen from Table I, among the six PRG patients who did not receive a transplant, three relapsed within 3 months of diagnosis. This suggests that a proportion of patients do not remain in CR1 long enough to receive a transplant. Accepting this, the data could result from a difference in the patient groups or suggest an advantage for BMT in CR1 for Ph+ ALL, particularly in the PRG.

When comparing the donor-type for those transplanted in CR1, the 3-year OS and EFS for MRD were 45% (17–71%) and for MUD were OS 74% (45–89%) and EFS 68% (39–85%) (P = 0·1 for both EFS and OS).

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

Though the trial made several changes, the overall survival in our group is a considerable improvement over that reported for children with Ph+ ALL in the preceding UKALL XI trial (Hann et al, 2001a) and comparable with those achieved in other trials (Schrappe et al, 1998; Arico et al, 2002). The ability of using the peripheral blast count to identify a poor prognostic group in children with Ph+ ALL has been previously reported in a large series (Schrappe et al, 1998) and as part of a meta-analyses (Arico et al, 2000). The results of this trial show that a slow response to therapy, as defined by marrow blast clearance, also identifies a high-risk group of Ph+ ALL children.

The majority of our cases had one or more secondary chromosomal abnormalities. A recent study of 249 children with Ph+ ALL showed that secondary abnormalities were non-random (Heerema et al, 2004). While their presence per se did not correlate with prognosis, the presence of an extra Ph chromosome was associated with an improved survival while deletions of 9p and loss of 7/7p indicated a worse outcome. This correlates with our observations that loss of 9p was associated with a poor initial response to treatment whereas those with an extra Ph chromosome were more likely to be good responders.

A number of factors could have contributed to the improvement in survival. Intensification of therapy has been reported to improve the outcome of Ph+ ALL (Arico et al, 2002) and those treated on the ALL 97/99 were treated with augmented BFM-type therapy prior to BMT. Additional factors that may have contributed to the better survival of Ph+ ALL patients in MRC ALL 97 are improvements in supportive and post-transplant care as well as an increase in the proportion of children being transplanted.

The BFM-AIEOP group reported a favourable outcome for those who received a MRD transplant over other donors (Schrappe et al, 1998) and the recommendation for MRD-only transplant for Ph positive ALL was subsequently supported by meta-analysed data (Arico et al, 2000). However, the successful use of a MUD for Ph+ ALL was reported around the same time from groups in the UK and USA (Sierra et al, 1997; Marks et al, 1998). In this study, the overall transplant outcome is comparable with that observed by the BFM/AIEOP group for MRD and outcome after a transplant in CR1 with a MUD was not inferior to that obtained with a MRD. If, as suggested, BMT in CR1 improves the outcome in Ph+ ALL, then the use of unrelated donors (Sharathkumar et al, 2004) will allow more children to be transplanted. However, the transplant-related mortality in our study was 19% and this needs to improve if we are to potentially improve outcome in the high-risk group.

Not all children with Ph+ ALL require a BMT. Both in this study and in the BFM/AIEOP study, there are children with Ph+ ALL who remain in long-term remission without being transplanted. These are all children who showed a favourable early response to treatment as defined by blast count, and comprised approximately 40% of the GRG. As we move into the molecular era (Pui & Campana, 2000), there is evidence to suggest that more sensitive evaluation of treatment response may clearly identify those who do not require a BMT. Cazzaniga et al (2002) showed that all children in their PRG Ph+ ALL remained persistently PCR positive throughout treatment. In their GRG, six of 13 patients attained molecular CR at the level of 10−4/−5 after 8 weeks of therapy. Of these, five were not transplanted and four remain in CCR (Cazzaniga et al, 2002). This suggests that real-time quantitative PCR monitoring may well be able to identify those who can be spared a potentially life-threatening BMT.

Conversely, there are also patients who fail to go into remission. This is seen primarily in the PRG group. Of the PRG patients, five (25%) in this study and 14 (70%) in the BFM/AIEOP study (Schrappe et al, 1998) were not in remission at the end of induction. In a subsequent AIEOP study, similarly, four (80%) of five children in the PRG were primary non-responders (Arico et al, 2002). Is there an explanation for this apparent difference other than chance? In comparison with the BFM/AIEOP protocol at the end of the first week, other than steroids and age-adapted intrathecal therapy, a child on the MRC protocol will also have received a single dose of daunorubicin and vincristine as well as two doses of l-asparaginase. Because of the changes in chemotherapy in ALL 97, we were able to examine the possible effects of dexamethasone and daunorubicin. While ALL 97 overall shows a significant survival advantage for those who received dexamethasone over prednisolone (Mitchell et al, 2004) this is not apparent in the Ph+ ALL cohort but the use of prednisolone postinduction for all HR1 patients will have weakened this comparison. We have previously reported that, while the use of daunorubicin in induction influences early marrow blast clearance in children with ALL, it does not improve outcome (Lilleyman et al, 1997). Given that the majority of those in the PRG received daunorubicin, its use does not appear to have influenced the early marrow response in our cohort, but, contrary to our previous observation (Lilleyman et al, 1997), seems to improve duration of remission. This suggests that early use of intensive chemotherapy in induction maybe beneficial for Ph+ ALL.

The Norton–Simon model (Norton & Simon, 1986) predicts the emergence of a refractory population of cells if a drug to which the majority of cells are not sensitive to is used as single agent. Thus the use of a single agent window in PRG Ph+ ALL, which has a high rate of evolution, may actually promote the development of a highly resistant clone. Arguably, it would be better to commence intensive therapy at diagnosis in this group of patients, but this observation needs further validation. The model also predicts that to maximize cell kill the most effective drugs must be used up front. Two studies have now reported over 95% remission rates when imatinib, the most potent anti-leukaemic agent for Ph+ cells (Druker et al, 2001), was added to standard induction therapy (Thomas et al, 2004; Towatari et al, 2004).

A challenging strategy for subsequent collaborative trials will be to screen all children with ALL rapidly for the BCR-ABL transcript at diagnosis. Imatinib should be included along with standard four-drug induction therapy. By monitoring the speed of response to treatment using quantitative molecular methods, it may then be possible to identify those who can be cured using intensive chemotherapy alone. Finally, safer BMT techniques are required if we are to improve the outcome of Ph+ ALL children in the PRG.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

Supported by the Medical Research Council (J.S.L, C.M); Cancer Research UK Clinical Research Fellowship (A.R); programme grants from Cancer Research UK (V.S, T.E) and the Leukaemia Research Fund (A.V.M). The authors wish to thank the Medical Research Council, UK for the funding of ALL 97. The authors are also grateful to the member laboratories of the UK Cancer Cytogenetics Group (UKCCG) for providing data and material.

References

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  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix
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Appendix

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Patients and diagnosis
  5. Treatment
  6. Analytical groups
  7. Statistical analysis
  8. Results
  9. Identification of Ph+ ALL patients
  10. Response to treatment
  11. Outcome according to risk groups
  12. Outcome according to induction therapy
  13. Outcome according to adverse cytogenetic features
  14. Postremission treatment
  15. Discussion
  16. Acknowledgements
  17. References
  18. Appendix

M Reid, K Windebank (Newcastle); M Caswell (Liverpool); P Darbyshire (Birmingham); S Dempsey (Belfast); OB Eden (Manchester); K Forman (Nottingham); B Gibson (Glasgow); A Oakhill (Bristol); I Hann, D Webb, J Chessells (GOS); C Harrison (Southampton); J Mann, F Hill (Birmingham); M Jenney (Llandough); D King (Aberdeen); S Kinsey (Leeds), S Mellor, M Orton (RMH); C Haworth, M Madi (Leicester); C Mitchell, J Durrant (Oxford); M Radford, M Morgan (Southampton); S Richards (CTSU); J Lilleyman, V Saha (Royal London); V Broadbent, J Simpson (Cambridge); O Smith (Dublin); R Stevens (Manchester); A Thomas (Edinburgh); A Vora (Sheffield); D Webb (GOS); A Will (Manchester); K Wheatley (BCTU).