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3303 Mitoxantrone Improves the Outcome of Children with Central Nervous System (CNS) Involvement at First Relapse of Acute Lymphoblastic Leukemia (ALL)-Results of the International ALLR3 Study

Program: Oral and Poster Abstracts
Session: Acute Myeloid Leukemia - Therapy, excluding Transplantation: Poster III
Monday, December 6, 2010, 6:00 PM-8:00 PM
Hall A3/A4 (Orange County Convention Center)
Poster Board III-82

Ashish Narayan Masurekar1*, Catriona Anne Parker1*, Satarupa Choudhuri2*, Carly Leighton2*, Jeremy Hancock3*, Rosemary Sutton, PhD4*, Anthony V. Moorman5, Phil Ancliff6*, Mary Morgan, MD7*, Nicholas Goulden8*, Nina Green9*, Tamas Revesz, MD, PhD, FRACP10*, Peter Hoogerbrugge, MD, PhD11, Philip Darbyshire12*, Sharon Love13* and Vaskar Saha1

1Children's Cancer Group, University of Manchester, Manchester, United Kingdom
2The Christie NHS Foundation Trust, The University of Manchester, Manchester, United Kingdom
3Bristol Genetics Laboratory, Bristol, United Kingdom
4Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, Sydney, Australia
5Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
6Great Ormond Street Hospital
7Dept of Haematology/Oncology, Southampton University Hospitals NHS Trust, Hampshire, United Kingdom
8Paediatric Haematology, Great Ormond Street Hospital, London, United Kingdom
9Youth and Women's Health Service
10Haematology Department, SA Pathology, North Adelaide, Australia
11Academic Hospital Nijmegen, Nijmegen, Netherlands
12Birmingham Children's Hospital
13Centre for Statistics, University of Oxford

Introduction: Despite improvement in frontline therapy in childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) relapse remains a significant clinical problem. The ALLR3 trial (ISCRTN 45724312) was designed specifically to address this issue with the use of drugs known to penetrate the CNS. The trial incorporated a randomization between Mitoxantrone and Idarubicin during induction. Mitoxantrone showed an early benefit in all patients resulting in closure of the randomization in December 2007 (ASH Annual Meeting Abstracts, Nov 2009; 114:3390). Subsequently all patients now receive Mitoxantrone. Here we report on the outcome of patients with isolated CNS relapse (iCNSr) or combined CNS relapse (involvement of CNS and bone marrow, cCNSr).

Methods: CNS involvement was defined as ≥5 WBC/µl with morphological evidence of blasts in the cerebrospinal fluid (CSF). Combined relapse (cCNSr) was defined as CNS disease with ≥ 5% blasts in the bone marrow. Time to relapse was classified as, Very Early: within 18 months of first diagnosis; Early: after 18 months of first diagnosis but within 6 months of stopping therapy and Late: more than 6 months after stopping therapy. All patients received 3 blocks of chemotherapy. Subsequently, allogenic stem cell transplant (allo-SCT) was offered to all very early relapses (iCNSr & cCNSr), early iCNSr (irrespective of immunophenotype), all T-cell cCNSr (irrespective of time to relapse) and early or late pre-B cCNSr that had a minimal residual disease level of ≥ 104 at the end of induction. All other patients were offered chemotherapy and cranial radiotherapy.

Results: Of a total of 330 relapsed patients, 102 (31%) had CNS involvement. Of these 63 (62%) had iCNSr and 39 (38%) had cCNSr. The incidence of CNS disease was higher in males (M:F, CNS relapses 2.5:1 vs all relapses 1.5:1). CNS relapses had a higher proportion of T-cell disease (pre B:T CNS relapses 3.6:1 vs all relapses 7.8:1]. The number of patients presenting in very early, early and late phases were 19 (19%), 55 (54%) and 28 (27%) respectively. All late iCNSr patients were males. Almost all late relapses (iCNSr and cCNSr) (27/28) were of a pre B phenotype. At the end of induction phase, 91/102 (89%) achieved complete remission (CR) and 82/102 (80%) remained in CR after 3 blocks of chemotherapy. The estimated 3-year overall survival (OS) and progression free survival (PFS) for all patients with CNS disease was 45.5% (95%CI 32.9, 58.0) & 43.4% (95%CI 32.0, 54.7) respectively. There were no significant differences in survival with respect to site of the disease (combined vs isolated), gender or immunophenotype (pre B vs T). As shown in Table 1, CNS relapse patients who received Mitoxantrone had a significantly improved outcome when compared to those who received Idarubicin. This was most evident in those who had i) iCNSr, ii) pre-B phenotype and iii) allo-SCT, when analyzed on an intention to treat basis. This represents a considerable improvement in outcome compared to the results obtained in these sub-groups of patients in the previous UK ALLR2 study (Roy A et.al. Br. J. Haem. 2005;130:67-75).

Conclusion: Mitoxantrone is highly effective in children with relapsed pre B ALL who have CNS involvement. As there were no other differences between patients treated on Mitoxantrone or Idarubicin, effective systemic therapy is as important as CNS directed therapy, if not more, in treating patients with CNS relapse.

Mitoxantrone

Idarubicin

p value

All CNS patients (n)

63

39

OS %

62.4 (CI 47.7, 77.1)

26.3 (CI 9.2, 43.3)

0.024

  PFS %

61.9 (CI 48.5, 72.2)

23.5 (CI 8.4, 38.5)

0.01

iCNS relapse (n)

39

24

OS %

61.4 (CI 43.3, 79.4)

11.2 (CI -8.4, 30.8)

0.029

  PFS %

56.6 (CI 38.3, 74.8)

11.0 (CI -7.3, 29.0)

0.096

cCNS relapse (n)

24

15

OS %

64.9 (CI 41.7, 88.0)

33.3 (CI 9.3, 57.2)

0.033

  PFS %

59.3 (CI 34.8, 83.8)

33.3 (CI 9.3, 57.2)

0.048

Pre-B (n)

47

33

OS %

68.1 (CI 51.8, 84.3)

28.2 (CI 9.7, 46.6)

0.014

  PFS %

65.8 (CI 50.9, 80.7)

24.3 (CI 8.4, 40.1)

0.006

T  (n)

16

6

OS %

44.0 (CI 15.9, 72.0)

33.3 (CI -4.3, 70.9)

0.455

  PFS %

41.4 (CI 24.7, 76.1)

33.3 (CI -4.3, 70.9)

0.717

Intended allo-SCT (n)

40

28

OS %

76.8 (CI 61.5, 92.1)

29.1 (CI 8.1, 50.0)

0.01

  PFS %

67.7 (CI 48.6, 86.7)

26.3 (CI 7.6, 44.9)

0.004

Actual allo-SCT (n)

32

21

OS %

85.4 (CI 72.0, 98.7)

33.4 (CI 09.6, 57.1)

0.003

  PFS %

77.8 (CI 58.9, 96.6)

31.2 (CI 11.4, 58.9)

0.004

Table 1: Shows outcome of patients treated on either Mitoxantrone or Idarubicin.  OS and PFS percentages are for 3 years; CI= 95% Confidence Interv

Disclosures: Off Label Use: Most drugs used in this protocol are off label as the majority of drugs used in childhood ALL are not liscensed for use in children..

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