Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial.
BACKGROUND
Although survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens.


METHODS
This open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1-18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10(-4) cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10(-4) cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312.


RESULTS
Of 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9-45·9) in the idarubicin group versus 64·6% (54·2-73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5-55·3) versus 69·0% (58·5-77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34-0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24-1·11, p=0·11).


CONCLUSIONS
As compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation.


BACKGROUND
Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.
Cancer Research UK Children's Cancer Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals Foundation Trust, Manchester, UK.
Catriona
C
Parker
Rachel
R
Waters
Carly
C
Leighton
Jeremy
J
Hancock
Rosemary
R
Sutton
Anthony V
AV
Moorman
Philip
P
Ancliff
Mary
M
Morgan
Ashish
A
Masurekar
Nicholas
N
Goulden
Nina
N
Green
Tamas
T
Révész
Philip
P
Darbyshire
Sharon
S
Love
Vaskar
V
Saha
D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use*; D007223:Infant; D053208:Kaplan-Meier Estimate; D007958:Leukocyte Count; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D008942:Mitoxantrone / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012008:Recurrence; D018570:Risk Assessment; D016896:Treatment Outcome; D006113:United Kingdom; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014750:Vincristine / Q000008:administration & dosage
D000903:Antibiotics, Antineoplastic; D003561:Cytarabine; D011092:Polyethylene Glycols; D014750:Vincristine; D005047:Etoposide; C042705:pegaspargase; D003907:Dexamethasone; D003520:Cyclophosphamide; D008942:Mitoxantrone; D015122:Mercaptopurine; D001215:Asparaginase; D014740:Vidarabine; C024352:fludarabine; D008727:Methotrexate; D015255:Idarubicin