Improved outcome of allogeneic haemopoietic stem celltransplantation for children with philadelphia positive acutelymphoblastic leukaemia

Although the prognosis for children and young adults with

acute lymphoblastic leukaemia (ALL) is excellent after modern

intensive treatment, there are several small subgroups who

have a high risk of relapse with conventional chemotherapy

and are candidates for allogeneic haemopoietic stem cell

transplant (allo-HSCT) in first complete remission. One such

group is Philadelphia positive (Ph+ve) ALL, which has a poor

prognosis in both children and adults. It forms <5% of ALL

cases in children but the frequency increases with age to 20–

30% in adults. Although conventional chemotherapy can

induce remission in >90% of cases, the risk of relapse is

exceptionally high if the remission is not consolidated by an

allo-HSCT (Arico et al, 2000). Therefore, first complete

remission (CR1) allo-HSCT is currently recommended as

definitive treatment for all children with Ph+ ALL by the major

childhood ALL study groups.

Recently, however, a US Children’s Oncology Group trial

obtained an excellent early outcome, comparable to that after

allo-HSCT, following treatment with a combination of the

tyrosine kinase inhibitor (TKI), imatinib, and conventional

chemotherapy(Schultz et al, 2009). It is therefore likely that

CR1 allo-HSCT will in future be restricted to sub-groups who

show evidence of resistance to chemotherapy and TKIs.

Essential to identifying a sub-group in whom the benefit of

allo-HSCT might outweigh its risks is availability of data on

current outcomes after allo-HSCT using a related or alternative

donor. We report our experience of transplanting an unse-

lected group of consecutive patients with Ph+ acute leukaemia

diagnosed at our centre over a 12-year period with a minimum

of 12 months follow-up post-transplant.

Twelve patients with Ph +ve acute leukaemia (six boys and

six girls) were diagnosed and transplanted at our centre

between May 1998 and April 2010. Individual patient charac-

teristics are described in Table I. Ten patients had ALL, one

had acute myeloid leukaemia (AML) and one mixed pheno-

type acute leukaemia. Nine patients were in CR1 and three

were in CR2. Median age at diagnosis was 10 years (2Æ9–

13Æ4 years) and median white blood cell count at presentation

was 27Æ2 · 109/l (5Æ0–394Æ4). The median interval between

diagnosis and CR1 was 28 d (range 28–75 d). All the patients

received first-line treatment on the then current UK national

trial protocol. In addition, seven patients received imatinib

(six) or dasatinib (one) pre-transplant.

Of the three children who received transplant in CR2, two

did not receive a CR1 transplant because of lack of a suitable

donor and, in the remaining patient, the Ph-status was

determined only at relapse because the diagnostic karyotype

and fluorescent in situ hybridization failed. The relapses

occurred at 32, 38 and 48 months from diagnosis. All three

achieved CR2 after reinduction. One received chemotherapy,

one single agent imatinib and one a combination of both.

Table II shows individual patient details for the transplant

procedure and outcomes. The median interval between

remission and transplant was 6 months (range 1Æ7–

54 months). Three children received transplant from matched

related donors and nine from unrelated donors. No patient

died of regimen-related toxicity. Eleven children developed

steroid-responsive acute graft-versus-host disease (GVHD)

and one had limited chronic GVHD. Two patients experienced

a relapse post transplant. Patient 5 had an isolated pelvic

relapse 21 months after a matched related donor transplant

and is in a molecular remission 50 months following a second

transplant from a matched unrelated cord blood donor. She

received imatinib before and for 1 year after the second

transplant. Patient 3 relapsed 44 months after matched

unrelated donor transplant and subsequently received donor

lymphocyte infusion (DLI) and imatinib. He remains in CR3

more than 3 years from second relapse on maintenance

imatinib. All 12 patients are in CR at a median follow up of

3.6 years post-transplant (1Æ2–9 years).

As reported recently by St Jude’s, outcomes of transplant for

children with high risk leukaemia have improved significantly in

the last decade (Leung et al, 2011). We have witnessed a similar

improvement in outcome at our relatively small paediatric

transplant centre as a result of a decrease in transplant-related

mortality (TRM) to 0% after related donor and <10% after

alternative donor transplants (Sorour et al, 2009). For Ph+ ALL,

the results reported here are substantially better than that

reported in a similar number of patients who received an

unrelated donor transplant at a UK centre over a decade ago

(Marks et al, 1998). The improvement in outcome may partly be

a result of all our patients receiving TKIs at some stage, although

the influence of TKIs on transplant outcomes has been

inconsistent (Kebriaei et al, 2011; Rives et al, 2011). With

treatment-related mortality comparable to that associated with

intensive chemotherapy (Arico et al, 2000), CR1 transplant,

therefore, remains a legitimate option for sub-groups of Ph+

ALL who have a high risk of relapse due to resistance or

intolerance to chemotherapy and TKIs. If so, should the

eligibility for alternative donor transplant be restricted to a

Correspondence

ª 2011 Blackwell Publishing Ltd 261British Journal of Haematology, 2012, 157, 249–277

cohort with a higher risk of relapse than would be eligible for a

related donor transplant? Our experience would suggest

otherwise, given that the nine patients in our cohort who

received an unrelated donor transplant remain alive and in CR,

one after DLI and imatinib for post-transplant relapse.

Furthermore, 70% of eligible patients lack a related donor and

Table II. Transplant details and outcome.

Patient

Remission

status BMT Conditioning

Interval between

CR & BMT (months) GVHD

Follow-up from

BMT (years)

Current

status

1 CR2 MUD Cy/TBI/Cam 48 Grade I skin/gut 9 CCR2

2 CR1 MUD Cy/TBI/Cam 9 Grade I skin 8Æ10 CCR1

3 CR2 MUD Cy/TBI/ATG 54 Grade I skin 7Æ4 CCR3

4 CR1 MUD Cy/TBI/ATG 5Æ5 Grade III skin 6Æ4 CCR1

5 CR2 MRD Cy/TBI/ATG 40 Grade II skin/gut 5Æ11 CCR3

6 CR1 MUD Cy/TBI/Cam 6 Grade I skin 3Æ7 CCR1

7 CR1 MUD Cy/TBI/ATG 4 Grade II skin 3Æ6 CCR1

8 CR1 MUD Cy/TBI/ATG 4 Grade I skin 2Æ8 CCR1

9 CR1 MRD Cy/TBI 1Æ7 Grade I skin 2Æ8 CCR1

10 CR1 MUD Cy/TBI/Cam 4 Chronic GVHD 1Æ6 CCR1

11 CR1 MRD Cy/TBI 4 No GVHD 1Æ3 CCR1

12 CR1 MUD Cy/TBI 6 Grade II skin/gut 1Æ2 CCR1

BMT, bone marrow transplant; CR, complete remission; GVHD, graft-versus-host disease CCR, continuing complete remission; MUD, matched

unrelated donor; MRD, matched related donor; Cy, cyclophosphamide; TBI, total body irradiation: Cam, Campath; ATG, anti-thymocyte globulin.

Table I. Patient Characteristics and treatment at diagnosis.

Patient

Age

(years)/sex Diagnosis

WBC at

Dx (109/l) Cytogenetics Treatment received

Interval Dx to

remission (days)

1 15/M ALL 6Æ34 46, XY, t(9;22)(q34;q11) UKALL 97 High risk protocol 34

2 17/F ALL 32Æ6 46, XX, t(9;22)(q34;q11) FRALLE 93 protocol 35

3 22/M ALL 8Æ4 47XY dup(1)(q23;q23) MRC ALL HR1 protocol 28

4 19/M ALL 6Æ5 46, XY, t(9;22)(q34;q11) UKALL 2003/EsPHALL at day 28 28

5 16/F ALL 7Æ9 46, XX, t(9;22)(q34;q11) ALL 97/99 28

6 7/M ALL 5Æ0 46, XY, t(9;22)(q34;q11) ADE · 2 – resistant, UKALL2003

Reg B

35

7 16/M MPAL 63Æ0 46, XY, t(9;22)(q34;q11) UKALL 2003 reg B/EsPhALL

cons. imatinib

28

8 9/F ALL 85Æ3 46, XX, t(9;22)(q34;q11) UKALL2003 reg B. BFM cons.

imatinib

28

9 15/F ALL 394Æ4 46, XX, t(9;22)(q34;q11) MRC AML 15 protocol,

FLAG-dasatinib

75

10 13/F AML 21Æ9 46, XX, t(9;22)(q34;q11) [1]/

48,idem,add(9)(p1),+add(9)

(p1),+der(22)t(9;22)(q34;q11)

[16]/46,XX[3]

UKALL 2003 reg B. imatinib 28

11 11/M ALL 225 46, XY, t(2;4)(p11q1),add(6)(q2),

t(9;22)(q34;q11.2),)15,

+mar[17]/46,XY[3]

UKALL 2003 reg B EsPhALL

cons. imatinib

28

12 15/F ALL 29Æ6 46, XX [20].nuc ish(ABL1x3,BCRx2)

(ALB1 con BCR x1)(78/143)

UKALL2003 EsPhALL cons.

imatinib

28

WBC, white blood cell count; Dx, diagnosis; ALL, acute lymphoblastic leukaemia; MPAL, mixed phenotypic acute leukaemia; AML, acute myeloid

leukaemia; FLAG, fludarabine, cytarabine; ADE, cytarabine, daunorubicin, etoposide; Reg, regimen; EsPhALL cons., European intergroup study on

post-induction treatment of Ph+ ALL consolidation; FRALLE, French-paediatric protocol; UKALL, UK National trial protocol for ALL; MRC,

Medical Research Council; BFM cons., Berlin-Frankfurt-Munster consolidation.

Correspondence

262 ª 2011 Blackwell Publishing LtdBritish Journal of Haematology, 2012, 157, 249–277

there is tentative evidence for a more potent graft-versus-leukaemia

effect from unrelated donor transplants (Cornelissen et al, 2001)

resulting in a comparable outcome despite a higher TRM.

TRM is not the sole consideration when comparing

the merits of transplant versus chemotherapy for high-risk

paediatric leukaemia and the late side effects of total body

irradiation (TBI) remain a major disadvantage of transplant

over chemotherapy. Most chemotherapy protocols recom-

mend cranial radiotherapy as standard central nervous system-

directed treatment for all patients with Ph+ ALL not eligible

for transplant (Schultz et al, 2009), but the burden of late side

effects is considerably higher following TBI than cranial

radiotherapy. However, just as the availability of TKIs might

allow cranial radiotherapy to be omitted from future chemo-

therapy protocols for Ph+ ALL, their use before and after

transplant might permit the development of novel reduced-

intensity conditioning regimens that do not contain TBI (Ram

et al, 2011).

Acknowledgements

AV designed the study, analysed the data and wrote the paper.

AG, AS and JW analysed the data. All authors contributed to

care of the patients included in this study and helped write the

paper.

Anshu Garg

Adhithya Sankar

Janet Williams

Emma Astwood

Jeanette Payne

Jenny Welch

Shan Rush

Julie Marples

Sharon Barrott

Ajay Vora

Department of Haematology, Sheffield Children’s Hospital, Sheffield, UK.

E-mail: ajay.vora@sch.nhs.uk

Keywords: acute lymphoblastic leukaemia (ALL), Philadelphia

positive acute leukaemia, children.

First published online 25 November 2011

doi: 10.1111/j.1365-2141.2011.08953.x

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