Acknowledgments: we thank
the research nurses Michelle
Bouvier and Hsien-Tzu Chen and
data manager Gresford Thomas
for their invaluable help in this
study; Helen Crawford, Bonnie
Larson, and Sue Carbonneau for
manuscript preparation; and
especially the patients and their
families, the transplantation
teams, physicians, nurses,
long-term follow-up team and
support personnel for their
dedicated care of patients in
this study.
Funding: this work was
supported by grants from
the National Institutes of
Health, Bethesda, MD (grants
P01CA018029, P01CA078902,
and P30CA015704). RR was a
recipient of a fellowship award
from the Davidoff Foundation.
Manuscript received on
January 7, 2011. Revised
version arrived on March 29,
2011. Manuscript accepted
on April 11, 2011.
Correspondence:
George E. Georges, M.D., Fred
Hutchinson Cancer Research
Center, 1100 Fairview Ave N,
D1-100; Seattle, WA, 98109
USA.
Phone: international
+1.206.6676886.
Fax: international
+1.206.6676124.
E-mail: ggeorges@fhcrc.org
Background
Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients
with acute lymphoblastic leukemia. However, the majority of older adults with acute lym-
phoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-mye-
loablative preparative regimen is a reasonable treatment option for this group. We sought to
determine the outcome of non-myeloablative conditioning and allogeneic transplantation in
patients with high-risk acute lymphoblastic leukemia.
Design and Methods
Fifty-one patients (median age 56 years) underwent allogeneic hematopoietic cell transplanta-
tion from sibling or unrelated donors after fludarabine and 2 Gray total body irradiation.
Twenty-five patients had Philadelphia chromosome-positive acute lymphoblastic leukemia.
Eighteen of these patients received post-grafting imatinib.
Results
With a median follow-up of 43 months, the 3-year overall survival was 34%. The 3-year
relapse/progression and non-relapse mortality rates were 40% and 28%, respectively. The
cumulative incidences of grades II and III-IV acute graft-versus-host disease were 53% and 6%,
respectively. The cumulative incidence of chronic graft-versus-host disease was 44%.
Hematopoietic cell transplantation in first complete remission and post-grafting imatinib were
associated with improved survival (P=0.005 and P=0.03, respectively). Three-year overall sur-
vival rates for patients with Philadelphia-negative acute lymphoblastic leukemia in first remis-
sion and beyond first remission were 52% and 8%, respectively. For patients with Philadelphia
chromosome-positive acute lymphoblastic leukemia in first remission who received post-graft-
ing imatinib, the 3-year overall survival rate was 62%; for the subgroup without evidence of
minimal residual disease at transplantation, the overall survival was 73%.
Conclusions
For patients with high-risk acute lymphoblastic leukemia in first complete remission, non-mye-
loablative conditioning and allogeneic hematopoietic cell transplantation, with post-grafting
imatinib for Philadelphia chromosome-positive disease, can result in favorable long-term sur-
vival. (Clinicaltrials.gov identifier: NCT0036738)
Key words: acute lymphoblastic leukemia, Philadelphia chromosome-positive, allogeneic
hematopoietic cell transplantation, non-myeloablative conditioning, imatinib.
Citation: Ram R, Storb R, Sandmaier BM, Maloney DG, Woolfrey A, Flowers MED, Maris MB,
Laport GG, Chauncey TR, Lange T, Langston AA, Storer B, and Georges GE. Non-myeloablative
conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute
lymphoblastic leukemia. Haematologica 2011;96(8):1113-1120.
doi:10.3324/haematol.2011.040261
©2011 Ferrata Storti Foundation. This is an open-access paper.
Non-myeloablative conditioning with allogeneic hematopoietic cell
transplantation for the treatment of high-risk acute lymphoblastic leukemia
Ron Ram,1 Rainer Storb,1,2 Brenda M. Sandmaier,1,2 David G. Maloney,1,2 Ann Woolfrey,1,2 Mary E. D. Flowers,1,2
Michael B. Maris,3 Ginna G. Laport,4 Thomas R. Chauncey,2,5 Thoralf Lange,6 Amelia A. Langston,7 Barry Storer,1,2
and George E. Georges1,2
1Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2University of Washington School of Medicine, Seattle, WA, USA;
3Rocky Mountain Cancer Center, Denver, CO, USA; 4Stanford University, Stanford, CA, USA; 5Veterans Affairs Puget Sound Health
Care System, Seattle, WA, USA; 6University of Leipzig, Leipzig, Germany, and 7Emory University, Atlanta, GA, USA
ABSTRACT
Original Articles
haematologica | 2011; 96(8) 1113

Introduction
Allogeneic hematopoietic cell transplantation (HCT)
with a myeloablative conditioning regimen is an estab-
lished potentially curative treatment for patients with
high-risk acute lymphoblastic leukemia (ALL).1,2 However,
many older adults with ALL are not candidates for high-
dose conditioning and HCT.3,4 The use of non-myeloabla-
tive conditioning with fludarabine and low-dose total
body irradiation can substantially decrease the toxicity of
the preparative regimen and extends the possible use of
allogeneic HCT to older or medically infirm patients.5,6
This approach relies primarily on potent graft-versus-
leukemia effects to prevent relapse of the disease. Other
reduced intensity regimens have been reported by investi-
gators for the treatment of patients with ALL.3,7-9 However,
relapse has remained a major problem following reduced
intensity conditioning regimens.
In recent years, imatinib mesylate, and subsequently the
newer tyrosine kinase inhibitors, dasatinib and nilotinib,
combined with chemotherapy were found to be very
effective for inducing disease remission in patients with
Philadelphia chromosome-positive (Ph+) ALL.10-13 Imatinib
therapy after allogeneic HCT was well tolerated and
improved relapse-free survival following myeloablative
conditioning compared to that in historical controls not
given imatinib therapy after HCT.14 A recent study
showed that patients with Ph+ ALL who received induc-
tion chemotherapy with imatinib followed by myeloabla-
tive conditioning and allogeneic HCT for Ph+ ALL in first
complete remission had a better overall survival com-
pared to patients who did not undergo HCT.15
Here we report on the multicenter experience with allo-
geneic HCT following non-myeloablative conditioning
with fludarabine and 2 Gray (Gy) total body irradiation for
patients with high-risk ALL. We identify risk factors for
disease relapse and mortality. We also describe the causes
of non-relapse mortality and the toxicity and efficacy of
post-HCT imatinib for patients with Ph+ ALL.
Design and Methods
Eligibility
This analysis includes 51 consecutive patients with ALL who
were prospectively enrolled and received non-myeloablative con-
ditioning followed by allogeneic HCT on sequential multi-institu-
tional protocols between February 1, 2000 and July 30, 2009. The
protocols were registered as National Cancer Institute clinical tri-
als. Patients treated with post-grafting imatinib were registered in
NCT00036738. Other patients were enrolled in sequential proto-
cols specific for donor type and with minor variations in planned
duration of post-grafting immunosuppression. Patients were treat-
ed at six centers with the Fred Hutchinson Cancer Research
Center (FHCRC) in Seattle (WA, USA) acting as the coordinating
center. All patients signed informed consent forms approved by
the local institutional review boards.
Patients with related or unrelated donors were eligible for non-
myeloablative conditioning if they were older than 55 or 50 years,
respectively. Younger patients were eligible if they had high-risk
ALL and co-morbid conditions that excluded them from myeloab-
lative conditioning or if they had disease relapse after a preceding
myeloablative HCT. Adult high-risk ALL was defined as beyond
first complete remission, or first complete remission and at least
one of the following: (i) age greater than 35 years, (ii) white blood
cell count greater than 30 109/L at diagnosis for B-cell ALL or
greater than 100 109/L at diagnosis for T-cell ALL, or (iii) Ph+ ALL
with t(9;22).2 Pediatric high-risk ALL was defined as beyond first
complete remission, or first complete remission and the addition
of one of the following: (i) failure to achieve complete remission
after the induction phase; (ii) t(9;22) or t(4;11) clonal abnormalities;
and (iii) poor response to prednisone in T-cell ALL with a white
blood cell count greater than 100 109/L.16
Pre-transplant characteristics
Patients referred for HCT in first complete remission had had a
median of three cycles (range, 3-4) of various standard
induction/intensification chemotherapy regimens.17-19 Pre-trans-
plant disease status was assessed within the 21 days prior to HCT.
Complete remission was defined according to standard morpho-
logical criteria as outlined by the International Working Group.20
For patients in complete remission, minimal residual disease was
assessed by multiparametric flow cytometry (minimum four-
color, cut-off level to establish minimal residual disease positivity
0.01%), karyotype analysis (G-banding) and fluorescence in situ
hybridization (FISH). Quantitative reverse transcriptase–poly-
merase chain reaction (RT-PCR) of p210 and p190 BCR/ABL
mRNA was not part of the work-up for minimal residual disease
in all of the patients with Ph+ ALL; thus, PCR results were not
included in assessment of minimal residual disease. All patients
and donors had high resolution HLA-allele level typing performed
for ten HLA alleles (HLA-A, B, C, DRB1 and DQB1). Patients
received grafts from the following donors: HLA identical siblings
(n=9), 10/10 HLA-allele matched unrelated donors (n=31), single
HLA allele mismatched unrelated donors (n=6) and single HLA-
antigen mismatched unrelated donors (n=5). Pre-transplant comor-
bidities were assessed retrospectively, using the HCT comorbidity
index (HCT-CI).21
Conditioning regimen and treatment plan
The conditioning regimen consisted of fludarabine (30
mg/m2/day on days -4 through -2 before HCT and 2 Gy total body
irradiation given at a dose of 0.07 to 0.1 Gy/min from linear accel-
erator sources on day 0.6 Patients received unmanipulated granu-
locyte colony-stimulating factor-mobilized peripheral blood stem
cells shortly after total body irradiation. One patient received an
unrelated bone marrow graft instead of peripheral blood stem
cells. Post-grafting immunosuppression consisted of combined
mycophenolate mofetil and a calcineurin inhibitor, cyclosporine or
tacrolimus, as previously described.5,22-25
All patients received intrathecal methotrexate (12 mg/dose or 6
mg/dose if given via an Ommaya reservoir) for central nervous
system prophylaxis, two doses pre-transplant (once per week) and
six doses post-transplant (starting on day +30, once every 2
weeks). All men received 16 Gy of testicular irradiation in eight
fractions during conditioning. All patients with a history of central
nervous system disease, three with Ph– and four with Ph+ ALL,
received cranio-spinal irradiation as part of the conditioning regi-
men.
The mean infused dose of peripheral blood stem cells was
8.5×106 CD34+ cells/kg body weight (range, 0.9×106-24.4×106).
Engraftment and donor chimerism were measured by variable
number tandem repeat of microsatellite markers at days 28, 56
and 84 after HCT.
Acute and chronic graft-versus-host disease (GVHD) were
assessed as described previously.6,26 Toxicities occurring within the
first 100 days were scored using the Common Terminology
Criteria for Adverse Events v3.0. Disease response after HCT was
monitored with standard marrow morphology, flow cytometry
and conventional cytogenetics, FISH and, if indicated, PCR for
R. Ram et al.
1114 haematologica | 2011; 96(8)

BCR-ABL transcripts.27 Disease responses were assessed 1, 3, 6, 12
and 24 months after HCT and/or as clinically indicated.
Patients with Philadelphia chromosome-positive acute
lymphoblastic leukemia
Twenty-five patients had the Ph+ cytogenetic abnormality
detected at diagnosis. After the introduction of imatinib, 18
patients enrolled in a study evaluating the safety and efficacy of
incorporating post-grafting imatinib into the treatment regimen.
Patients were initiated on imatinib at a dose of 600 mg orally once
daily either by their referring physician or at the transplant center
before enrollment on the study. Imatinib was stopped on day –2
before HCT to avoid interaction with engraftment of donor
hematopoietic cells. Imatinib was recommenced at a dose of 400-
600 mg daily after HCT when the absolute neutrophil count was
greater than 0.5 109/L or on day +15 if there was no neutropenia.
Imatinib was continued for at least 1 year after HCT, unless there
was toxicity or disease progression; all patients received imatibib
for at least 1 month. Dose reduction of imatinib was allowed for
mitigation of side effects/ toxicities.
Causes of death
In patients who relapsed or progressed with ALL, relapse/pro-
gression was listed as the primary cause of death regardless of
other associated events. Relapse was defined as recurrence of
malignancy based on one or more of the following parameters:
marrow morphology, flow cytometry, cytogenetic studies, includ-
ing FISH, or RT-PCR for BCR/ABL transcripts. All deaths occurring
in the absence of relapse/progression were considered non-relapse
mortality.
Statistical analysis
Data were analyzed as of October 1, 2010. Overall survival was
estimated using the Kaplan-Meier method. Cumulative incidence
estimates were calculated for acute and chronic GVHD, relapse
and non-relapse mortality. Death was treated as a competing risk
in the analyses of relapse/progression and acute and chronic
GVHD. Relapse/progression was treated as a competing risk
when analyzing non-relapse mortality. Cox regression was used
for univariate analyses of risk factors for all time-to-event end
points. For each analysis, hazard ratios (HR) and 95% confidence
intervals (95% CI) are given together with P values for compar-
isons with the reference category. All P values are derived from
likelihood ratio statistics and are two-sided.
Results
Fifty-one patients underwent allogeneic HCT. All had
high-risk ALL including 19 who were beyond first com-
plete remission. Six patients were under 18 years of age (1
in first complete remission and 5 beyond first complete
remission). Table 1 summarizes the patients’ characteris-
tics. Twenty-five patients had Ph+ ALL. Of these, 18
received post-grafting imatinib (Table 2). The median fol-
low-up for surviving patients was 43 (range, 14-98)
months.
Engraftment
Fifty patients achieved sustained donor engraftment.
One patient with Ph+ ALL had non-fatal primary graft
rejection. This patient received an HLA matched unrelated
marrow graft with a dose of 0.9×106/kg CD34+ cells. After
graft rejection, this patient was treated with imatinib,
chose not to undergo a second HCT, relapsed and died 20
months after HCT. The median donor CD3+ T-cell
chimerism levels for the 50 peripheral blood stem cells
recipients at day 28 and day 84 were 79 (range, 15-100)%
and 88 (range, 48-100)%, respectively. The chimerism and
engraftment patterns were not different in patients treated
with imatinib.
Graft-versus-host disease
By day 120 after HCT, 53% of patients had developed
grade II acute GVHD and 6% had developed grades III-IV
acute GVHD (Figure 1A). Among the patients who
received HLA-identical sibling, HLA-allele-matched unre-
lated donor, and HLA-allele/antigen mismatched unrelat-
ed grafts, the overall incidences of grade II-IV acute GVHD
were 33%, 50% and 91%, respectively. The cumulative
incidence of chronic extensive GVHD at 3 years was 42%
(Figure 1B).
Among the patients with Ph+ ALL treated with post-
grafting imatinib (n=18), ten (56%) developed grade II-IV
acute GVHD. There was no significant difference between
the incidences of acute GVHD among patients who
received or did not receive imatinib (HR=0.65, 95% CI
0.3-1.4; P=0.25). Ten of the 18 patients (56%) developed
chronic extensive GVHD and five (28%) developed limit-
ed chronic GVHD. There was no significant difference in
the incidence of chronic GVHD among patients who
received or did not receive imatinib (HR=1.4, 95% CI 0.6-
3.3; P=0.45). Five patients (36%) developed chronic skin
GVHD while receiving imatinib treatment. Discont -
inuation of imatinib after HCT was not associated with
new onset or exacerbation of chronic GVHD.
Non-myeloablative transplantation for ALL patients
haematologica | 2011; 96(8) 1115
Table 1. Characteristics of ALL patients, disease and transplantation.
Characteristics Ph– ALL (n=26) Ph+ ALL (n=25)
Median age: years (range) 56 (8-65) 57 (38-69)
Disease status at time of HCT: n, (%)
CR1 without MRD 12 (46%) 13 (52%)
CR1 with MRD 1 (4%) 6 (24%)
>CR1 (CR2/CR3) 13 (50%) 5 (20%)
Persistent disease 0 1 (4%)
Months from diagnosis to HCT:
median, (range)
CR1 7.7 (4-10.7) 7.6 (4.4-10.9)
Beyond CR1 30.6 (10.7-90.7) 38.7 (8.9-126.1)
History of myeloablative HCT (%) 4 (15%) 2 (8%)
HCT-CI1 (%)
0-1 9/17 (53%) 14/18 (78%)
2 8/17 (47%) 4/18 (22%)
Recipient gender (male/female) 11/15 16/9
Female donor to male recipient: (%) 5 (19%) 6 (24%)
Donor type: (%)
HLA-identical sibling 4 (15%) 5 (20%)
Unrelated HLA matched 14 (54%) 17 (68%)
1 HLA allele mismatched 3 (12%) 3 (12%)
1 HLA antigen mismatched 5 (19%) 0
Cell dose × 106 CD34+ cells/kg: 8.8 (2-20.2) 8.2 (0.9-24.4)
median, (range)
Cell source (marrow/PBSC) 0/26 1/25
ALL: acute lymphoblastic leukemia, CR1: first complete remission, HCT-CI: hematopoiet-
ic cell transplantation comorbidity index, MRD: minimal residual disease, PBSC: periph-
eral blood stem cells, Ph: Philadelphia chromosome. 1Data were available for 17 Ph–
ALL patients and for 18 Ph+ ALL patients.

Non-relapse mortality
The rate of non-relapse mortality at 3 years after HCT
among all patients was 28% (Figure 1C). The following
causes of death were included under non-relapse mortali-
ty: GVHD (n=4), GVHD-associated infections (n=8), sep-
sis (n=1), congestive heart failure (n=1) and suicide (n=1).
There was no significant difference in non-relapse mortal-
ity between patients who were or were not treated with
post-HCT imatinib (HR=0.5, 95% CI 0.2-1.5; P=0.20). The
four deaths in the imatinib group were due to GVHD-
associated infections: bacterial pneumonia, sepsis with
pancreatitis, respiratory syncytial virus pneumonia and
community-acquired H1N1 viral pneumonia.
Disease relapse/progression
Among the 51 patients, 22 (43%) had relapse/progres-
sion at a median of 5 (range, 0.3 to 58) months after HCT.
None of the patients developed isolated central nervous
system relapse. None was treated with donor lymphocyte
infusion for disease relapse. The median time from the
diagnosis of relapse to death was 4 (range, 0.3-15) months
in the 20 patients who had died by the time of analysis.
Overall, the 3-year estimated probability of relapse/pro-
gression was 40%. Univariate analysis identified risk fac-
tors for relapse/progression (Table 3). Patients beyond first
complete remission at the time of HCT had a significantly
increased risk for relapse after HCT compared to those in
first complete remission (HR=3.9, 95% CI 1.6-9.5,
P=0.002). For Ph– ALL (n=26), the 3-year estimated relapse
rate for patients in or beyond first complete remission was
15% and 62%, respectively (Figure 2). For Ph+ ALL (n=25),
the 3-year estimated relapse rate for patients in and
beyond first complete remission was 32% and 67%,
respectively (Figure 2). Two patients with molecular evi-
dence of disease after transplantation were included as
having disease relapse. For patients with Ph+ ALL, evi-
R. Ram et al.
1116 haematologica | 2011; 96(8)
Table 2. Characteristics of Ph+ ALL patients treated with imatinib after HCT.
Patient # Time Therapy Additional Status at MRD at Duration of GVHD while Chronic Alive/ Disease Overall
from Dx pre HCT cytogenetic HCT HCT, imatinib on imatinib GVHD after dead status at last survival since
to HCT abn. assessed post-HCT stopping follow-up/ HCT
(months) pre-HCT by (months) imatinib cause of death (months)
1 6 HyperCVAD no CR1 no 11 no n/a dead Rel 13
2 9 HyperCVAD no CR1 yes- FCM 8 yes n/a dead NRM 28
3 6 Larson no CR1 no 50 yes n/a alive CR 73
4 7 HyperCVAD yes CR1 no 11 yes n/a dead NRM 12
5 5 HyperCVAD no CR1 no 24 yes no alive CR 77
6 5 HyperCVAD yes CR1 no 6 yes n/a dead Rel 8
7 10 GMALL yes CR1 no 4 yes n/a alive CR 90
8 4 HyperCVAD no CR1 no 24 no no alive PCR 62
Relapse –CR
on dasatinib
9 8 HyperCVAD no CR1 no 45 yes n/a alive CR 62
10 9 HyperCVAD yes CR1 yes-FCM 3 yes n/a dead Rel 5
11 5 HyperCVAD yes CR1 no 18 yes n/a alive CR 33
12 9 Linker no CR1 no 12 no yes alive CR 39
13 8 HyperCVAD yes CR1 no 3 no yes alive CR 32
14 82 HyperCVAD, yes CR2 yes-FCM 14 yes n/a alive PCR Relapse – 27
HCT, HyperCVAD CR on nilotinib
15 12 HyperCVAD no CR2 yes-FISH 10 yes n/a dead NRM 10
16 11 HyperCVAD, MEI yes CR2 yes-FCM 16 no no dead Rel 16
17 91 SWOG 9400, yes CR3 no 6 yes n/a dead NRM 7
HCT, HyperCVAD,
HIDAC, DA
18 10 HyperCVAD no Relapse yes-Histo 14 yes n/a dead Rel 14
All patients except UPN 10 had imatinib therapy prior to HCT. UPN 16 had central nervous system (CNS) disease prior to HCT. None of the patients had CNS disease relapse after
HCT. Two patients (UPN 8 and 14) had disease relapse after HCT detected by PCR and flow cytometry and are currently alive in molecular complete remission (CR). UPN 8 dis-
continued imatinib 24 months after HCT, had disease relapse detected by PCR for the BCR/ABL p190 transcript at 43 months. This patient was retreated with imatinib, achieved a
molecular CR within 2 months and remained PCR negative for 12 months. At 57 months after HCT, molecular relapse was again detected by BCR/ABL p190 transcript and flow
cytometry of the bone marrow with 0.35% aberrant blasts, and therapy was changed to dasatinib. Molecular CR was achieved within 1 month and the patient has remained in
molecular CR for 5 months. UPN14 had molecular relapse detected by PCR for BCR/ABL p190 transcript and flow cytometry 0.002% at 17 months after HCT. This patient was
treated with nilotinib, achieved a molecular CR within 2 months and has remained in molecular CR for 8 months. Additional cytogenetic abnormalities at any time prior to allogeneic
HCT: UPN4: complex (+7, +8, -11, -12, der 19), UPN6: complex (+2, +5,+10,+16,+18,+19,+21,+X), UPN7:, t(9;14), UPN10: (+8,+22),UPN11:(-7), UPN13:(-7), UPN14: complex(+2, -9,-
11,-Y, inv7p13, +13p11), UPN16: complex (+5,+8,+8,+13,+14,+20), UPN17: complex (-7,-8,-13,-16,+11). Twelve patients were initiated/maintained on imatinib 600 mg daily, six
patients were initiated/maintained on imatinib 400 mg daily (UPN 9, 11, 12, 13,16, 17). UPN 2, 5 and 12 had subsequent imatinib dose reductions to 200-400 mg daily. Ph+ ALL:
Philadelphia chromosome positive acute lymphoblastic leukemia; HCT: hematopoietic cell transplantation; Dx: diagnosis; MRD: minimal residual disease; CNS: central nervous sys-
tem; GVHD: graft versus host disease; HyperCVAD: hyper fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; GMALL: German multicenter ALL regimen;
MEI: mitoxantrone, etoposide, ifosfamide; DA: daunorubicin, ara-c; HIDAC: high dose ara-c; CR: complete remission; FISH: fluorescent in situ hybridization; FCM: flow cytometry; Histo:
conventional histology. n/a: not applicable.

dence of additional cytogenetic abnormalities at diagnosis
was associated, at a borderline level, with an increased
risk of relapse after HCT (HR=3.4, 95% CI 0.9-13;
P=0.06).
Survival
The estimated 3-year overall survival rate among the 51
patients was 34%. Relapse was the primary cause of death
(n=20, 57% of all deaths). Univariate analysis performed
for the entire cohort identified the disease status of being
beyond first complete remission as the only significant
factor associated with increased mortality (HR=2.7, 95%
CI 1.4-5.3; P=0.005) (Table 3). Other factors (donor source,
acute or chronic GVHD) were not significantly associated
with increased mortality. The 3-year overall survival rates
for patients with Ph– ALL in and beyond first complete
remission were 52% and 8%, respectively, (HR=3.4, 95%
CI 1.3-9.1; P=0.01) (Figure 3A). Excluding the six pediatric
patients, the 3-year overall survival rates for patients in
and beyond first complete remission were 48% and 0%,
respectively (HR=4.5, 95% CI 1.4-15.1, P=0.01).
Among patients with Ph+ ALL, treatment with post-
HCT imatinib was associated with significantly decreased
mortality (HR=0.3, 95% CI 0.1-0.9; P=0.03) (Table 3). The
3-year overall survival rates for patients with Ph+ ALL who
were in first complete remission or beyond first complete
remission were 47% and 17%, respectively; however, this
difference did not reach statistical significance (HR=1.8,
95% CI 0.6-5.4; P=0.32). For patients in first complete
remission who received post-grafting imatinib, the 3-year
overall survival rate was 62% (Figure 3B, Table 2); for the
subgroup that had no evidence of minimal residual disease
at HCT, the overall survival rate was 73%. Additional
cytogenetic abnormalities (other than Ph+) detected at
diagnosis, showed a trend to be associated with increased
mortality (HR=2.0, 95% CI 0.7-5.5; P=0.19).
Outcomes of patients under 18 years old
Six patients with Ph– ALL were younger than 18 years
at the time of HCT: these patients had a median age of 11
(range, 8-16) years. Four had relapsed after a prior allo-
graft, one was in first complete remission and one in third
complete remission. Two patients received HLA-antigen
mismatched unrelated grafts. All five patients beyond first
complete remission relapsed (3 of them within 6 months).
All patients developed acute GVHD. The single patient in
first complete remission is currently alive at 88 months
post-HCT.
Outcomes of patients aged over 60 years
Sixteen patients (31%) were older than 60 years at the
time of HCT: the median age of these patients was 63
(range, 61-69) years. Six of the 16 (38%) patients died from
causes other than relapse and four (25%) had disease
relapse. Of the nine patients with Ph– ALL, two in first
complete remission are currently alive after more than 2.1
years. Among patients with Ph+ ALL (n=7), the estimated
3-year overall survival rate was 57%.
Imatinib toxicity
The median duration of post-HCT imatinib treatment
was 11.5 (range, 3-50) months (Table 2). The drug was
given at a daily dose ranging between 200 mg and 600 mg.
Table 3. Prognostic factors for relapse and mortality using univariate analysis.
Relapse Mortality
HR (95% CI) P HR (95% CI) P
Entire cohort (n=51)
Beyond CR1 3.9 (1.6-9.5) 0.002 2.7 (1.4-5.3) 0.005
Matched URD (vs. sibling) 1.1 (0.3-3.9) 0.86 0.6 (0.2-1.3) 0.16
Acute GVHD1 0.5 (0.2-1.2) 0.11 0.9 (0.4-1.7) 0.69
Chronic GVHD1 0.7 (0.2-2.3) 0.53 1.0 (0.5-2.2) 0.98
Ph+ ALL (n=26)
Beyond CR1 2.4 (0.7-8.6) 0.20 1.8 (0.6-5.4) 0.32
Additional cytogenetic 3.4 (0.9-13) 0.06 2.0 (0.7-5.5) 0.19
abnormalities
Treatment with imatinib 0.4 (0.1-1.5) 0.20 0.3 (0.1-0.9) 0.03
ALL: acute lymphoblastic leukemia, CI: confidence interval, Beyond CR1: disease stage greater
than first complete remission, GVHD: graft-versus-host disease, HR: hazard ratio, Ph: Philadelphia
chromosome, URD: unrelated donor. 1Analyzed as a time-dependent covariate.
Non-myeloablative transplantation for ALL patients
haematologica | 2011; 96(8) 1117
Figure 1. Cumulative incidences (n=51) of (A) acute graft-versus-
host disease (GVHD): 53% grade II, 6% grade III-IV; (B) chronic
extensive GVHD: 42% incidence at 3 years; (C) non-relapse mortal-
ity, 28% incidence at 3 years.
A
B
C
Pe
rce
nt Grade 2
Grade 3/4
Pe
rce
nt
Pe
rce
nt
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
Acute GVHD
Chronic GVHD
Non-relapse mortality
0 1 2 3 4 5 6 7
Years from transplant
0 6 12 18 24 30 36
Months from transplant
0 20 40 60 80 100 120
Days from transplant

Dose modifications were made in three patients. In gener-
al, imatinib was well tolerated. Three patients (17%) dis-
continued imatinib because of adverse events, all of which
were reversible (two cases of gastrointestinal toxicity and
one of recurrent pleural effusion).
Discussion
Despite improvements in therapy, mortality from high-
risk ALL has not decreased substantially in older patients.
Two large prospective trials and meta-analyses summariz-
ing the results of the previous controlled trials showed
that allogeneic HCT after myeloablative conditioning
improved the outcome of adult patients with high-risk
ALL.2,28-31 However, in patients with high-risk disease, a
survival advantage was demonstrated only up to 35 years
of age.2,32 Developing HCT approaches for older or med-
ically infirm patients with ALL has remained challenging.
While the outcome for patients not undergoing allogeneic
HCT is very poor, those who proceed with myeloablative
conditioning followed by HCT have an unacceptably high
rate of non-relapse mortality.2,33 This multicenter study
addressed the problem of non-relapse mortality in older
and medically infirm patients by using a non-myeloabla-
tive conditioning regimen consisting of fludarabine and 2
Gy total body irradiation which depended on allogeneic
graft-versus-leukemia effects for curing high-risk ALL.
We observed that overall survival was significantly
improved for patients who underwent HCT early in the
course of their disease. For Ph– ALL patients in first com-
plete remission, the 3-year overall survival rate was 52%,
while that for patients beyond first complete remission
was only 8%, primarily due to increased disease relapse.
Other investigators who used various reduced intensity
regimens and allogeneic HCT have reported 2 to 3-year
overall survival rates ranging from 20%-61%.3,7-9,34 The
heterogeneous study outcomes might have been due to
differences in disease status and characteristics of the HCT
donors. The positive impact of early allogeneic HCT in
first complete remission was reported by Mohty et al. and
Bachanova et al.3,7 Our study confirms both this finding
and the poor overall survival of patients beyond first com-
plete remission. Furthermore, the sustained survival
plateau among patients in first complete remission
demonstrates that durable, long-term disease-free survival
may be achieved for a majority of Ph+ ALL patients treat-
ed with imatinib as well as for Ph– ALL patients. Thus, in
patients for whom allogeneic HCT is considered as post-
remission therapy, it should be recommended early rather
than late in the course of the disease.
The most striking finding of our study was the favorable
overall survival rate of 47% at 3 years for Ph+ patients in
first complete remission given imatinib after HCT. The
overall survival rate was 73% for those Ph+ patients in
first complete remission without minimal residual disease
at HCT. Relapse was increased in Ph+ patients: (i) with
additional cytogenetic abnormalities, (ii) beyond first
complete remission, and (iii) in first complete remission
with minimal residual disease at HCT. The latter two fac-
tors were not statistically significant probably because of
the inclusion of patients before the availability of imatinib.
Age did not appear to limit the feasibility of our treatment
protocol. For example, Ph+ ALL patients older than 60
years had a 3-year overall survival rate of 57%.
Incorporation of imatinib and newer tyrosine kinase
inhibitors into the various phases of the treatment for Ph+
ALL patients has reshaped the therapeutic algorithm.
Thomas et al. showed that the incorporation of imatinib
into induction chemotherapy resulted in a 2-year overall
survival of 56%, which included patients who proceeded
to myeloablative allogeneic HCT.35,36 A single center study
showed that incorporation of imatinib into induction
R. Ram et al.
1118 haematologica | 2011; 96(8)
Figure 2. Cumulative relapse rate for Ph– ALL, in first complete
remission (CR1) (n=13) versus beyond CR1 (n=13) and Ph+ ALL CR1
(n=19) versus beyond CR1 (n=6). Molecular disease relapse (PCR or
flow cytometry positive) without morphological evidence of disease
was included as relapse.
Figure 3. Overall survival for (A) Ph– ALL, in first complete remission
(CR1) (n=13) versus beyond CR1 (n=13) and (B) Ph+ ALL patients
receiving imatinib after hematopoietic cell transplantation, CR1
(n=13) versus beyond CR1 (n=5).
A
B
Ph+, CR1
Ph+, >CR1
Ph-, CR1
Ph-, >CR1
CR1
>CR1
Censored
CR1
>CR1
Censored
Pe
rce
nt
re
lap
se
/p
ro
gr
es
sio
n
Pe
rce
nt
su
rv
iva
l
100
80
60
40
20
0
100
80
60
40
20
0
Pe
rce
nt
su
rv
iva
l
100
80
60
40
20
0
0 1 2 3 4 5 6 7
Years from transplant 0 1 2 3 4 5 6 7Years from transplant
0 1 2 3 4 5 6 7

chemotherapy with subsequent myeloablative condition-
ing and allogeneic HCT resulted in a 3-year overall sur-
vival rate of 78%.37 Currently, data for patients treated
with tyrosine kinase inhibitors and not proceeding to allo-
geneic HCT are scarce. A recent phase II trial showed a 2-
year estimated overall survival rate of 64% for patients
receiving only dasatinib in addition to induction and main-
tenance chemotherapy.38 While these results are encourag-
ing, a median follow-up of 14 months in this cohort is
probably too short to enable recommendation of alterna-
tive approaches to allogeneic HCT. Thus, it is possible that
the major role of tyrosine kinase inhibitors, both in med-
ically “fit” and in medically infirm or older patients, is to
allow a greater proportion of patients to receive allogeneic
HCT. Consequently, particularly in the setting of non-
myeloablative HCT, the use of tyrosine kinase inhibitors
post-transplant appears to provide a sufficient level of dis-
ease control until the development of a graft-versus-
leukemia effect.
In accordance with published data for imatinib after
myeloablative HCT,14 we showed that imatinib was safe
in the context of non-myeloablative allogeneic HCT and
was generally well tolerated. In contrast to recent publica-
tions that suggested a role for imatinib in the prevention
and treatment of chronic skin GVHD,39,40 we did not
observe a significant decrease in the incidence of chronic
GVHD, nor did we detect an increase in the incidence of
chronic GVHD after the discontinuation of imatinib,
although the number of patients in our study was limited.
The optimal duration of post-HCT imatinib therapy is
unknown. In our study, patients were treated with ima-
tinib for varying periods, according to preferences of the
physicians and patients. Two patients were successfully
treated with a second-generation tyrosine kinase inhibitor
after detection of molecular relapse. Although the follow-
up for these two patients was limited, the findings suggest
that close follow-up of patients is necessary and that
molecular complete remission can be achieved after detec-
tion of molecular relapse. Until data from larger cohorts
are available, we would cautiously recommend continuing
treatment with tyrosine kinase inhibitors indefinitely
unless there is evidence of either toxicity or disease
relapse.
Although the incidence of acute GVHD was high, most
cases were grade II and only 6% of patients developed
grades III-IV acute GVHD. In accordance with previous
publications, the highest incidence of acute GVHD
occurred in patients receiving HLA-mismatched grafts.24 In
contrast to a previous study, we did not observe an inverse
correlation between chronic GVHD and relapse.41 In part,
this could be explained by the fact that relapse in our
cohort occurred early after HCT (at a median of 5 months)
particularly among patients with disease beyond first
complete remission.
Since ALL is relatively rare in adults, our study was lim-
ited by the relatively small number of patients and the fact
that enrollment occurred over a nearly 10-year period.
Nonetheless, we showed that non-myeloablative condi-
tioning and allogeneic HCT is a very feasible and effective
treatment option for high-risk ALL patients in first com-
plete remission. For Ph+ ALL patients in first complete
remission, imatinib should be given after HCT since it
appears to improve overall survival. Our results suggest
that non-myeloablative conditioning and allogeneic HCT
is a potentially curative treatment option for older or med-
ically infirm patients with high-risk ALL in first complete
remission. For patients beyond first complete remission,
post-HCT maintenance with novel agents should be
explored and studies addressing the role of next generation
tyrosine kinase inhibitors given after HCT are warranted.
Authorship and Disclosures
The information provided by the authors about contributions from
persons listed as authors and in acknowledgments is available with
the full text of this paper at www.haematologica.org.
Financial and other disclosures provided by the authors using the
ICMJE (www.icmje.org) Uniform Format for Disclosure of
Competing Interests are also available at www.haematologica.org.
Non-myeloablative transplantation for ALL patients
haematologica | 2011; 96(8) 1119
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