Current Treatment of Philadelphia Chromosome–Positive
Acute Lymphoblastic Leukemia
Adele K. Fielding1
1University College London, London, United Kingdom
The author discusses both the standards of care and more controversial areas in the treatment of Philadelphia
chromosome–positive acute lymphoblastic leukemia.
Introduction
Approximately one-fourth of adult acute lymphoblastic leukemia
(ALL) expresses the oncogenic protein BCR-ABL1 that results from
the t (9;22) chromosome translocation known as the Philadelphia
(Ph) chromosome. Formerly seen as a poorly tractable therapeutic
problem, Ph-positive (Ph!) ALL is associated with at least a 10%
lower chance of complete remission (CR) than Ph-negative (Ph")
disease and with an extremely poor prognosis overall, with a median
survival of 8 months.2 However, multiple clinical trials of BCR-ABL–
specific tyrosine kinase inhibitors (TKIs) have conclusively demon-
strated significantly superior initial responses resulting in higher CR
rates without additional toxicity. In addition, studies are beginning
to suggest that better long-term outcomes are also possible. There is
little or no evidence to date that allogeneic hematopoetic stem cell
transplantation (alloHCST), the toxic mainstay of treatment for this
disease, is yet (or will ever be) a dispensable part of therapy.
Therefore, key challenges in the treatment of Ph! ALL are the
selection of appropriate pretransplantation therapy, the minimiza-
tion of transplantation toxicity, the correct use of TKIs after
transplantation, and the appropriate use of and response to BCR-
ABLmonitoring. The increasing use of reduced-intensity condition-
ing (RIC) as preparative regimens may mean that one or more of the
key challenges will require a different response to that which is
appropriate when myeloablative regimens are used, but there are
few data to guide practice at present.
Because there are already several clear and cogent summaries of
how to treat Ph! ALL, this review summarizes older data and
noncontroversial areas of practice succinctly and focuses in more
detail upon areas of practical concern for which there are emerging
data or as yet no clear right answer. “Long-term” outcomes within
this article refer to studies with# 3 years of follow-up. When the
follow-up was less than this, either the time of reporting is quoted or
the term “short-term” outcome is used.
Remission induction
Table 1 shows the outcomes of numerous studies in de-novo Ph!
ALL in which a TKI has been added to conventional induction
therapy, given in conjunction with steroid alone, or given with less
intensive chemotherapy. CR rates are, notably, always# 90%.
Based on these data, there is now no rationale for omitting a TKI
from the initial induction treatment.
Instead, it is now logical to ask whether there is a rationale for
reducing or omitting cytotoxic agents from initial induction treat-
ment altogether. Several studies have reported, at least in abstract
form, the initial outcome of giving TKIs without with only minimal
chemotherapy.3-5 Taking a closer look at the CR rates reported, most
studies show that the major reason that a 100% CR rate is not
reported are deaths during induction. However, where chemo-
therapy is minimized or excluded, studies have reported 100%
CR.3-5 The first study in which this occurred was a Gruppo Italiano
Malattie Ematologiche dell’Adulto (GIMEMA) study reported by
Vignetti et al, all the more remarkable in that the study included an
older population with a median age of 69. Given imatinib 800 mg/d
along with prednisolone 40 mg/m2 for 45 days, all patients entered
remission with minimal toxicity and many did not need hospitaliza-
tion. Median survival was 20 months. A further study from the
GIMEMA group, LAL1205, which has been published to date only
in abstract form,3 has investigated the use of dasatinib and steroids
without chemotherapy as induction in patients from the age of 18
upwards. Once again, the CR rate was 100% with no induction
fatalities. These results are impressive and represent a clear and
remarkable improvement in the short-term fate of patients with
Ph! ALL.
However, the long-term outcome of a chemotherapy-free induction
strategy is not assessable. The patients reported by Vignetti et al
were not eligible for “definitive therapy,” namely BM transplanta-
tion, due to their advanced age. Participants in the second study
reported by Foa et al went off study after induction, obscuring the
effects on long-term outcome. Two further studies, neither of which
has been published to date, have reported short-term, preliminary
results when TKIs were added to “minimal” chemotherapy. The
French Group for Research in Adult Acute Lymphoblastic Leuke-
mia (GRAALL) study5 carried out a randomized comparison of
imatinib combined with hyper-CVAD (cyclophosphamide, vincris-
tine, doxorubicin, dexamethasone) against imatinib with dexameth-
asone and vincristine only during induction. Notably, 100% of
patients in the “minimal” chemotherapy arm achieved CR, but only
96% in the more intensively treated arm, with toxicity being
responsible for the difference. Again, the long-term consequences
of a minimal chemotherapy induction strategy are as yet unclear, but
this important study will eventually shed light on the issue. A further
study from the European Working Group on ALL (EWALL)
collaboration led by Philippe Rousselot6 has examined a dasatinib
and “minimal chemotherapy” induction regimen (namely vincris-
tine and dexamethasone) combination in older individuals with a
median age of 69. Of the 71 subjects enrolled, 90% achieved CR.
Median overall survival (OS) was 27 months. Most relapses were
associated with the T315I BCR-ABL mutation. It is not clear
whether the addition of a more intensive chemotherapy regimen
might have prevented that.
Despite the initial appeal of no-chemotherapy strategies, recent
murine data suggest that the addition of chemotherapy to dasatinib
CURRENT MANAGEMENT ISSUES IN ACUTE LYMPHOCYTIC LEUKEMIA
Hematology 2011 231

treatment might help to prevent the emergence of dasatinib-resistant
mutations in BCR-ABL.7 Ph! ALL was generated in mice by
administering Arf-null, BCR-ABL–expressing cells. The disease
responded to treatment with dasatinib, but after prolonged dasatinib
exposure, BCR-ABL kinase domain mutations were detected in mice
with relapsed disease. When dexamethasone and L-asparaginase
were added to the therapy, there was a more prolonged clinical
response that was accompanied by the emergence of significantly
fewer kinase domain mutations. There is probably an optimal
intensity of chemotherapy for combination with TKIs that helps to
maintain medium- to long-term responses without adding therapy-
related mortality. As yet, that optimal combination is not clear, but it
is a pressing and important question for future consideration.
Another very pertinent question concerns the optimal choice of TKI
for induction. Dasatinib, offering simultaneous inhibition of both
tyrosine and SRC kinases, may theoretically holds out more promise
of long-term benefit than imatinib, which offers TK inhibition
alone. No randomized study has yet been carried out. Some
inferences regarding remission induction can be made from existing
studies. When given with steroid alone, we have already seen that
both agents can generate 100% CR rates. In relation to chemo-
therapy combinations, the MD Anderson group have studied
sequentially the combination of both imatinib (n$ 20)8 and dasat-
inib (100 mg/d, n$ 35)9 with the hyper-CVAD regimen. Percent-
age CR rates were similar, 93% and 94%, respectively, but with
such small numbers the comparison is barely robust. Neither study
reported outcomes beyond 24 months, which approximately reaches
the median survival times generally reported for TKI-containing
regimens. At the time of reporting of the dasatinib combination, the
median survival was not yet reached. However, with 75% disease-
free survival (DFS) at 20 months for imatinib and a projected 64%
DFS at 24 months for dasatinib, there is no immediate short- to
medium-term survival difference apparent. However, the dasatinib
combination regimen generated 16 episodes of bleeding and
8 episodes of pleural effusion, whereas the specific toxicity of
imatinib was minimal. Results of studies to date cannot explicitly
justify adding dasatinib to chemotherapy combinations for the
therapy of de-novo Ph! ALL.
Postremission therapy and allogeneic stem cell
transplantation
Although many studies show early benefits to TKI treatment,
evidence of a survival benefit has only recently emerged, because
many of the initial studies reported early. However, a recent Italian
study10 of 94 patients treated with imatinib and chemotherapy
included a nonrandomized, historical control group receiving the
same chemotherapy treatment but without imatinib. The patients
who received imatinib in their regimen had a 5-year OS of 38%
compared with 23% in the control group. A second study including
a control group receiving the same chemotherapy without imatinib
has been carried out by the UK National Cancer Research Institute
(NCRI)/US Eastern Cooperative Oncology Group (ECOG) collabo-
ration and has recently been reported in abstract form.11 There was a
large, apparently imatinib-attributable difference in outcome: OS
was 23% in the pre-imatinib cohort compared with 43% when
imatinib was added. However, careful analysis revealed a consider-
ably higher rate of alloHSCT in the imatinib cohort. On examination
of the comparative outcomes of those not receiving imatinib, the
addition of imatinib to chemotherapy in the absence of myeloabla-
tive alloHSCT did not result in a significant survival benefit, even
when patients who did not survive in remission to the median time
to alloHSCT were excluded. Therefore, at least after imatinib-
containing induction regimens, myeloablative alloHSCT does not
appear to be dispensable if the optimal long-term outcome is to be
achieved. Where imatinib-based induction and myeloablative al-
loHSCT are combined, excellent 3-year OS rates are to be expected
despite the risk of myeloablative alloHSCT. The relevant 3-year OS
in UKALL12/E2993 was 59%. An abstract report on successive
German Multi Centre ALL (GMALL) studies in Ph! ALL12 also
Table 1. Studies of TKI in de novo Ph! ALL
Study Study group Drug, dose, mg N CR, %
Transplantation
rate, % OS
Published studies
Thomas8 MD Anderson Im 400 20 93 50 75% at 20 mo
Yanada29 JALSG Im 600 80 96 61 75% at 1 year
Wassmann38 GMALL Im 4–600 92 95 77 36% (alternating schedule)
43% (concurrent schedule
at 2 y
De Labarathe39 GRAALL Im 600 45 96 48 65% at 18 mo
Vignetti4 GIMEMA Im 800 30 100 N/A 74% at 12 mo
Ottman27 GMALL Im 600 55 96 (imatinib) 50
(chemo)
N/A 42% at 24 mo
Ribera40 PETHEMA Im 400 30 90 70 30% at 4 y
Bassan41 NILG Im 59 92 63 38% at 5 y
Schultz14 COG Im 340/m2 92 Not stated N/A* 80% (EFS) at 3 y
Ravandi9 MD Anderson Das 50 bd (or 100 od) 35 94 N/A as not part
of protocol
64% at 24 mo
Unpublished studies
Fielding11 NCRI/ECOG Im 600 145 95 44 43% at 3 y
Chalandon5 GRAALL Im 800 188ˆ 100 (imatinib DIV)
96 (imatinib
hyper-CVAD)
62 62% at 2 y
Foa3 GIMEMA Das 70 bd 12 weeks 48 100 N/S 80,7% at 10 mo
Rousselot6 EWALL Das 140 od (100 od
# 70 y)
71 90 N/A Median 27.1 mo
JALSG indicates Japanese Adult Leukaemia Study Group; NILG, Northern Italian Leukaemia Group; COG, Children’s Oncology Group; NCRI/ECOG, UK National Cancer
Research Institute/Eastern Cooperative Oncology Group; Im, imatinib; and Das, dasatinib.
232 American Society of Hematology

revealed that excellent outcomes can be achieved with myeloabla-
tive alloHSCT when an imatinib-based induction is used; OS at
3 years was 72%. A recent Japanese Adult Leukaemia Study Group
also reports a 3-year OS probability of 65% after imatinib-based
induction and myeloablative alloHSCT.13 Both the UK/ECOG and
GMALL studies reported a poor outcome when transplantation was
not achieved despite the inclusion of imatinib in the protocols.
A caveat to the nondispensability of alloHSCT has been raised by
the Children’s Oncology Group (COG),14 which carried out a study
in which patients up to the age of 21 were treated with imatinib
added to chemotherapy in cohorts, with the final cohort receiving
continuous imatinib. The protocol did not allow for matched
unrelated donor (MUD) alloHSCT. This decision, which differs
from recommendations given in all studies of adult Ph! ALL, was
based on an international study in children15 showing a 43%
treatment-related mortality (TRM) for MUD alloHSCT. Despite the
low relapse rate after MUD allo-HSCT, this unacceptably high
TRM negated a survival advantage when outcomes were compared
with those in children receiving chemotherapy alone. This policy
left a small cohort of children who received an imatinib/
chemotherapy combination without alloHSCT. There was a rela-
tively high rate of off-protocol MUD alloHSCT that makes data
interpretation more difficult. However, at 3 years, the outcomes for
those treated with imatinib/chemotherapy (n$ 25) compared favor-
ably to those treated with alloHSCT (n$ 21), with an 85% 3-year
DFS without alloHSCT. Although the study was neither designed
nor powered to answer the question of whether imatinib/
chemotherapy could replace sibling alloHSCT for children with Ph!
ALL, the data have introduced the hypothesis that children with Ph!
ALL can be treated successfully without alloHSCT. It will be very
important to look at the long-term follow-up of that study.
Nonmyeloablative (RIC) alloHSCT
Myeloablative alloHSCT carries considerable risk of TRM and is
not applicable to older individuals. Opinions vary on the upper age
limit for the procedure; in UKALL12/E2993, a very high TRM of
nearly 40% was observed in patients older than 35 years of age
receiving myeloablative allo-HSCT, resulting in a protocol limit of
40 years of age in the current UK NCRI study, UKALL14. In some
studies, patients are offered myeloablative alloHSCT up to the age
of 55 years. Not surprisingly, RIC is beginning to gain more
widespread use. Although prospective studies of this approach are
ongoing, none has been reported to date, which means that
published, retrospective reports must be interpreted with caution
due to the problems of selection bias and immortal time bias. To
confound interpretation of the data further, most published series
include patients beyond CR1 and none is confined to Ph! ALL.
Nonetheless, a realistic overview of what can be achieved using this
approach in high-risk ALL is beginning to emerge. A summary of
reports of RIC approaches to the treatment of Ph! ALL is given in
Table 2. The numbers of patients treated in CR1 only are recorded in
the table because the clearest theme running through all of the
studies to date is that if patients with relapsed or resistant disease or
beyond CR1 undergo transplantation, the outcomes are dismal and
the mortality very high.
However, when considering this approach as used in CR1, a few
key, positive messages emerge. First, RIC regimens can be used
with an acceptable TRM in patients who are typically older than
those suitable for a myeloablative approach. Median ages reported
range from 38 to 50 years, and TRM in more recent studies, which
include more patients in CR1, is consistently between 20% and
30%. No particular conditioning regimen can be deduced to be
optimal yet. cGVHD rates are high, and there is insufficient
evidence to determine whether the high rate of GVHD is positively
associated with a better disease-related outcome. There are likely to
be trials using approaches in which conditioning regimens that have
a lower risk of cGVHD are investigated. In summary, nonmyeloab-
lative alloHSCT approaches appear promising, offering DFS rates
in Ph! ALL, which, where overtly specified, appear to be higher
than could be obtained with chemotherapy and imatinib alone and
are in line with what has been achieved using myeloablative
approaches. A comparative study of European Group for Blood and
Marrow Transplantation (EBMT) registry reports of the outcome of
myeloablative versus RIC alloHSCT in patients with ALL confirms
this impression.16 Indeed, in a multivariate analysis, the type of
conditioning regimen was not significantly associated with leukemia-
free survival. RIC approaches should be vigorously pursued as part
of prospective studies in order to define their role in ALL. In Ph!
ALL in particular, inquiry into the role of TKIs after alloHSCT is
vital. The forthcoming study from the UK NCRI, UKALL14, will
assign all patients with ALL 40 years of age or more than to a
nonmyeloablative approach with fludarabine, melphalan, and alem-
tuzumab in an attempt to obtain good disease control with less GVHD.
What treatment should be offered to patients with
poor donor options?
Despite initial responses, long-term outcomes, at least in adults,
remain unsatisfactory when TKI/chemotherapy combinations are
used without alloHSCT. Does this justify the use of alternative,
higher-risk donor and conditioning options in relation to 1 or
Table 2. Studies of RIC alloHSCT regimens in patients with ALL
Study
Center/
registry/
multicenter
Median
age (total
population) Ph!, N
Ph!
CR1, N
Conditioning
regimen TKI after alloHSCT?
TRM, %
(total
population)
CGVHD, %
(total
population)
OS Ph!
subgroup
Arnold42 M 38 11 3 Flu/Bu % ATG No 45 46 N/S
Martino43 M 50 11 3 Various N/S 23 72 N/S
Mohty44 R 38 37 N/S Various N/S 28 37 N/S
Stein41 S 47.5 9 6 Flu/Mel Various 21.5 86 N/A
Bachanova45 S 49 14 10 Flu/Cy/TBI 2 Gy Only for morphological
or to relapse
27 45 N/A
Ram24 S 57 25 19 Flu/TBI 2 Gy 4–600 mg daily, upon
count recovery, for
1 year
28 44 62% 3 y
N/A indicates numbers too small/status at transplantation too various to give a single figure; N/S, not specified; TBI, total body irradiation; Flu, fludarabine; Bu, bulsuphan; Mel,
melphalan; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; S, single; R, registry; andM, multicenter.
Hematology 2011 233

2 antigen mismatch unrelated donor (MMUD), haploidentical and
umbilical cord blood (UCB) transplantations? It is hard to be sure
exactly how the higher risk of TRM balances against the increased
risk of relapse. Haploidentical alloHSCT often results in a very high
TRM. A series including 60 cases of ALL has been reported, of
which, only 15 cases were Ph! and approximately half were beyond
CR1. These data have been recently reviewed in detail.17 UCB
HSCT in adults has a higher TRM than MUD HSCT. However,
where the donor is not fully matched, UCB is arguably a better
option.18 A recent report from Japan19 documented 8 adults with
Ph! ALL who, after a median of 26 months of follow-up, had an
estimated 3-year OS of 100% and a leukemia-free survival of 85%.
However, this is a small number of patients and such good results
with minimal toxicity are not typical of cord blood transplantations
in adults. As counterbalance, a recent report from the University
College London (UCL) group of 50 patients receiving MMUD
grafts after RIC for a variety of disorders, including acute leuke-
mias, there was no difference in 3-year OS (53% vs 49%, P $ .44)
between fully matched and MMUD even though the mismatch
occurred at the antigenic level in 40 cases.20
Balanced against the toxicity of high-risk transplantation ap-
proaches is the high risk of relapse without a alloHSCT and the lack
of clear guidance in the literature as to how best to combine TKIs
with consolidation and maintenance therapy or whether to continue
with TKI treatment after the typical maintenance period of 2 years.
Given the difficulty in balancing these approaches for patients with
poor donor options, these situations must currently be tackled on a
case-by-case basis, taking into careful account the preferences and
expectations of the patient.
Autologous transplantation
Autologous transplantation remains a possible therapeutic option in
ALL. Although the large randomized controlled trial UKALL12/
EOCG299321 demonstrated inferiority compared with continued
chemotherapy, there may be circumstances when clinicians con-
sider this to be a reasonable option. There are anecdotal reports of
good outcomes when autologous transplantation is used when
minimal residual disease is not present before the procedure. There
are no data on how best to use TKIs after autologous transplantation
for Ph! ALL.
The role of TKIs after alloHSCT
A very important and as yet unanswered question concerns whether
TKIs should be administered after alloHSCT and under what
circumstances. Programa para el Estudio de la Terape´utica en
Hemopatı´a Maligna (PETHEMA) study reported that imatinib was
poorly tolerated after myeloablative alloHSCT; only 62% of
patients were able to start at median of 3.9 months after alloHSCT,
and many patients required discontinuation or dose reduction. An
ongoing GMALL study for which preliminary results have only
been reported in abstract form22 randomized patients after HSCT to
either “up-front” imatinib beginning at 3 months after alloHSCT
wherever possible or imatinib started only upon any BCR-ABL
reappearance. This study also reported poor tolerance of imatinib
when given early after alloHSCT. In contrast, most patients who
started imatinib after the detection of BCR-ABL had a prompt
suppression of BCR-ABL in response to the drug, and to date there is
no difference in outcome between the groups. A small, nonrandom-
ized, single-center study from the University of Minnesota23 showed
a trend toward improved outcome in patients who could be treated
with imatinib in the pre- and posttransplantation period after
cyclophosphamide and TBI myeloablative conditioning. Similarly,
Ram et al24 reported that imatinib given for a median duration of
11.5 months after RIC with fludarabine and 2 Gy of TBI (which was
relatively well tolerated after transplantation, with only 3 of
18 patients needing to stop the drug) was associated with signifi-
cantly reduced mortality on univariate analysis, although the effect
on relapse was not statistically significant. There is insufficient
evidence to conclude that imatinib should be given to all patients
after alloHSCT. However, outside of a clinical trial, careful
consideration should be given on a patient-by-patient basis as to
whether and when to start imatinib. Regular and quantitative
BCR-ABL monitoring in an accredited laboratory is strictly neces-
sary if an expectant policy is to be followed. The next section
provides additional information about BCR-ABL monitoring in Ph!
ALL.
Role of BCR-ABL monitoring in Ph! ALL
Real-time PCR BCR-ABL quantification is often used to monitor
minimal residual disease in patients with Ph! ALL, but optimal
practice and interpretation of results is unclear. In addition, while
there is considerable standardization of methodology for p210
quantification, there is less standardization for p190 quantification.
Within the European Union, the European Study Group’s (ESG)
twice annual quality control rounds are helping to define a
pan-European standard, but at the time of writing there is still
variation in practice and reporting among participating laboratories.
In addition, there are conflicting reports on the association between
an initial decrease in BCR-ABL transcript level and long-term
outcome. In the “pre-imatinib” era, good correlation between
BCR-ABL transcript levels and outcome has been reported.25,26 After
clinical trials including TKIs, BCR-ABL transcript levels have also
been correlated with response.27 Unlike in chronic myeloid leuke-
mia, there is no consensus on what represents an optimal response.
However, Lee et al28 were able to demonstrate that a 3-log reduction
in BCR-ABL transcripts after 1 month of imatinib treatment strongly
predicted a reduced relapse risk.28 In contrast, Yanada et al29
observed no association between rapid achievement of BCR-ABL
negativity and long-term outcome after an initial imatinib/
chemotherapy induction regimen.29 The long-term outcome in
relation to BCR-ABL response to induction is hard to predict. There
are now 2 reports that low-level subclones harbor point mutations in
the BCR-ABL kinase domain at diagnosis.30,31 Both studies demon-
strated that the presence of mutated BCR-ABL clones at diagnosis
did not preclude an initial “good” BCR-ABL response. Pragmati-
cally, imatinib- and dasatinib-containing regimens can be expected
to generate complete clinical response in 95%-100% of patients.
Eligible patients will be treated with alloHSCT wherever possible,
and for these patients, BCR-ABL monitoring early in the course of
the disease is unlikely to change practice at present. For patients not
receiving alloHSCT, serial monitoring during initial therapy is of
more relevance because it might prompt a switch of therapy before
hematological relapse.
In the future, when there is more understanding of the kinetics of
BCR-ABL mutations, a wider range of TKIs available, and a greater
understanding of the relationship between different BCR-ABL
subclones and long-term outcomes, the practice of BCR-ABL and
serial mutation monitoring is likely to change and to assume greater
importance. However, currently, the most immediate impact of
BCR-ABL monitoring is on therapy after alloHSCT, when various
manipulations such as immunosuppression reduction, addition of
TKIs, and the use of donor lymphocyte infusions are readily
available. However, there are few data to guide strategy. The
234 American Society of Hematology

optimal frequency of monitoring is not clear. The relationship
between BCR-ABL reappearance and relapse been recently ques-
tioned in a report of 2 cases of very long-term (# 10 years)
remissions in the presence of persistent low-level p190 BCR-ABL in
2 patients with Ph! ALL after treatment with autologous HSCT
without any subsequent further antileukemic therapy.32 However, at
present, the balance of evidence suggests that BCR-ABL should be
monitored after alloHSCT and that reemergence of BCR-ABL is a
rational basis for intervention.
Resistance to TKIs and novel agents for use in this
scenario
The emergence of BCR-ABL mutations that confer resistance to one
or more TKIs is likely to confirm the clinical observations from
large trials showing that, without transplantation, long-term DFS
survival is not optimal. Mutations are most frequent within the
kinase domain of BCR-ABL and can occur within the A (activation)
loop, the P (ATP-binding) loop, or at the so-called “gatekeeper”
residue, threonine 315. We have already noted in this review that
more than 1/3 of patients present with small subpopulations
containing BCR-ABL mutations. Mutations can also be acquired or
emerge under the selection pressure of TKI treatment.33 The
emergence of mutations is associated with hematological relapse,
as demonstrated in the EWALL study in older patients, in whom
serial monitoring for the T315I mutation showed that a rise
of # 0.1% was always associated with relapse.6 However, the
interval between rise of T315I signal and clinical relapse was 1-3
months in half of the patients and concomitant in the other half,
giving little leeway for intervention in many. Novel agents active
in the setting of the T315I and other mutations are under clinical
study. Ponatinib (AP24534) is a potent pan-BCR-ABL inhibitor
with activity against all tested imatinib-resistant mutants,
including T315. In a recent phase 1 study,34 most patients had
chronic myeloid leukemia, but 3 had Ph! ALL. Elevation of
pancreatic enzymes and pancreatitis were dose-limiting toxici-
ties. A dose of 45 mg orally was chosen for further study. At this
dose, responses were observed in patients with the T315I
mutation whose disease was resistant to dasatinib.
Blinatumomab, a bispecific, T-cell-engaging antibody binding CD19
and Cd3, is a novel agent with potential for efficacy in patients at
high risk of disease relapse. In a small study of patients with a
persistent or new appearance of molecularly determined ALL, an
80% response rate was observed (n$ 21).35 Relapse-free survival at
a median follow-up of 405 days was reported without the need for
additional chemotherapy. Of particular interest, activity was also
demonstrable in Ph! patients with a detectable T315I tyrosine
kinase domain. Overall, therapy was well tolerated, and patients
who received alloHSCT (n$ 8) all remain alive and in remission
after transplantation (median follow-up of 434 days). Based on
these preliminary data, blinatumomab is being studied in a Euro-
pean pivotal phase 2 study (with US centers participating) in
minimal residual disease–positive adult ALL. Table 3 summarizes
several ongoing trials of TKIs and other novel agents in Ph!ALL. A
more exhaustive account of all trials in Ph! ALL can be found at
www.clinicaltrials.gov.
It follows that BCR-ABL mutation screening is likely to be the most
clinically relevant in patients who are receiving TKIs without or
without chemotherapy but without the possibility of a “definitive”
alloHSCT procedure. An increase in BCR-ABL level or a frank
hematological relapse is an important trigger for mutational analysis
to select an available TKI to which the patient’s disease might still
be sensitive or to seek a clinical trial of a novel agent.
Table 3. Ongoing studies of novel agents in Ph! ALL
Title Inclusion criteria Sponsor
Clinical trial.gov
identifier
A Phase 1/2 Study of SNDX-275 in
CombinationWith Imatinib for
Relapsed/Refractory Philadelphia
Chromosome Positive Acute
Lymphoblastic Leukemia
Primary refractory or relapsed disease Sidney Kimmel Comprehensive
Cancer Center, USA
NCT01383447
A Phase 1/2 Study Of SKI-606
(Bosutinib) In Philadelphia
Chromosome Positive Leukemias
Ph!CML or Ph! ALL who are primarily
refractory to full-dose imatinib (600 mg),
have disease progression/relapse while on
full-dose imatinib, or are intolerant of any
dose of imatinib
Pfizer NCT00261846
A Phase I Dose Escalation of
MK0457 in CombinationWith
Dasatinib in PatientsWith Chronic
Myelogenous Leukemia and
Philadelphia Chromosome-Positive
Acute Lymphoblastic Leukemia
Patients must have CML or Ph! ALL; patients
must be at least 3 mo from the start of
dasatinib therapy and currently receiving
dasatinib therapy for CML or Ph! ALL and
evaluable for hematologic response prior to
entering the study
Merck NCT00500006
To determine the dose of dasatinib
that can be safely administered
with cytarabine, and high-dose
mitoxantrone in patients with Ph!
ALL/lymphoid blast crisis of known
chronic myelogenous leukemia
Previously untreated and treated adult patients
(!18 y of age) with a diagnosis of Ph! ALL
Memorial Sloan-Kettering Cancer
Center, USA
NCT00940524
NilotinibWith Chemotherapy for the
Treatment of Philadelphia
Chromosome Positive Acute
Lymphoblastic Leukemia (ALLPhi)
Newly diagnosed ALL or acute mixed lineage
leukemia; positive for Bcr-Abl fusion
transcript (Ph! disease) by RT-PCR
Asan Medical Center, Korea NCT00844298
Hematology 2011 235

Relapsed Ph! ALL
Relapsed ALL is a notoriously difficult clinical problem, and
outcomes are typically extremely poor.36 CR2 is possible in only
& 50% of chemotherapy-treated patients. Many younger patients
with Ph! ALL will have already received alloHSCT, making
salvage harder and with more toxicity, particularly if chemotherapy
reinduction is under consideration. However, a phase 2 study of
dasatinib 140 mg/d in patients who relapsed after imatinib-
containing regimens demonstrated that approximately half of the
patients could achieve a CR2 with modest toxicity. However,
median remission duration was only 3.3 months. Under these
circumstances, a second allo-HSCT might be considered. A case
report37 shows a positive outcome for a patient who received
dasatinib followed by a RIC alloHSCT after imatinib and myeloab-
lative alloHSCT failed to control the disease. All reports of
alloHSCT show a very much less than ideal outcome in patients
beyond CR1. However, many of these were reported before the
advent of TKIs, which might, in selected circumstances, allow for
second definitive transplantation procedures.
Disclosures
Conflict-of-interest disclosure: The author declares no competing
financial interests. Off-label drug use: None disclosed.
Correspondence
Adele K. Fielding, University College London Medical School,
London, United Kingdom; Phone: !44 207 794 0500; Fax: !44
207 830 2833; e-mail: a.fielding@ucl.ac.uk.
References
1. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an
independent prognostic factor in adult acute lymphoblastic
leukemia (ALL): analysis of cytogenetic data from patients
treated on the Medical Research Council (MRC) UKALLXII/
Eastern Cooperative Oncology Group (ECOG) 2993 trial.
Blood. 2007;109:3189-3197.
2. Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV.
Philadelphia positive acute lymphoblastic leukemia in adults:
age distribution, BCR breakpoint and prognostic significance.
Leukemia. 1991;5:196-199.
3. Foa R, Vitale A, Guarini A, et al. Dasatinib as first line
treatment of adult Ph! acute lymphoblastic leukemia (ALL)
patients. Final results of the GIMEMA LAL1205 study [Ab-
stract]. Blood. 2008;112:305.
4. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids
induces complete remissions and prolonged survival in elderly
Philadelphia chromosome-positive patients with acute lympho-
blastic leukemia without additional chemotherapy: results of
the Gruppo Italiano Malattie Ematologiche dell’Adulto
(GIMEMA) LAL0201-B protocol. Blood. 2007;109:3676-
3678.
5. Chalandon Y Thomas X, Hayette S, et al. First results of the
GRAAPH-2005 study in younger adult patients with de novo
Philadelphia positive acute lymphoblastic leukemia [Abstract].
Blood. 2008;112:12.
6. Rousselot P, Hayette S, Re´cher C, et al. Dasatinib (Sprycel®)
and low intensity chemotherapy for first-line treatment in
elderly patients with de novo Philadelphia positive ALL
(EWALL-PH-01): kinetics of response, resistance and prognos-
tic significance [Abstract]. Blood. 2010;116:1204.
7. Boulos N, Mulder HL, Calabrese CR, et al. Chemotherapeutic
agents circumvent emergence of dasatinib-resistant BCR-ABL
kinase mutations in a precise mouse model of Philadelphia
chromosome-positive acute lymphoblastic leukemia. Blood.
2011;117(13):3585-3595.
8. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia
chromosome-positive acute lymphocytic leukemia with hyper-
CVAD and imatinib mesylate. Blood. 2004;103:4396-4407.
9. Ravandi F, O’Brien S, Thomas D, et al. First report of phase 2
study of dasatinib with hyper-CVAD for the frontline treatment
of patients with Philadelphia chromosome-positive (Ph!) acute
lymphoblastic leukemia. Blood. 2010;116(12):2070-2077.
10. Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased
imatinib pulses improve long-term outcome of adult patients
with Philadelphia chromosome-positive acute lymphoblastic
leukemia: Northern Italy Leukemia Group protocol 09/00.
J Clin Oncol. 2010;28(22):3644-3652.
11. Fielding AK, Buck G, Lazarus H, et al. Imatinib significantly
enhances long-term outcomes in Philadelphia positive acute
lymphoblastic leukaemia; final results of the UKALLXII/
ECOG2993 Trial [Abstract]. Blood. 2010;116:493.
12. Pfeifer H, Goekbuget N, Volp C, et al. Long-term outcome of
335 adult patients receiving different schedules of imatinib and
chemotherapy as front-line treatment for Philadelphia-positive
acute lymphoblastic leukemia (Ph! ALL) [Abstract]. Blood.
2010;116:173.
13. Mizuta S, Matsuo K, Yagasaki F, et al. Pre-transplant imatinib-
based therapy improves the outcome of allogeneic hematopoi-
etic stem cell transplantation for BCR-ABL-positive acute
lymphoblastic leukemia. Leukemia. 2011;25(1):41-47.
14. Schultz K, Bowman W, Aledo A, et al. Improved early
event-free survival with imatinib in Philadelphia chromosome-
positive acute lymphoblastic leukemia: A Children’s Oncology
Group Study. J Clin Oncol. 2009;27(31):5175-5181.
15. Arico` M, Valsecchi MG, Camitta B, et al. Outcome of
treatment in children with Philadelphia chromosome-positive
acute lymphoblastic leukemia. N Engl J Med. 2000;342:998-
1006.
16. Mohty M, Labopin M, Volin L, et al. Reduced-intensity versus
conventional myeloablative conditioning allogeneic stem cell
transplantation for patients with acute lymphoblastic leukemia:
a retrospective study from the European Group for Blood and
Marrow Transplantation. Blood. 2010;116(22):4439-4443.
17. Marks DI, Aversa F, Lazarus HM. Alternative donor trans-
plants for adult acute lymphoblastic leukaemia: a comparison of
the three major options. BoneMarrow Transplant. 2006;38:467-
475.
18. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after
transplantation of cord blood or bone marrow from unrelated
donors in adults with leukemia. N Engl J Med. 2004;351:2265-
2275.
19. Onishi Y, Sasaki O, Ichikawa S, et al. Favorable outcome of
unrelated cord blood transplantation for philadelphia chromo-
some-positive acute lymphoblastic leukemia. Biol Blood Mar-
row Transplant. 2011;17(7):1093-1097.
20. Mead AJ, Thomson KJ, Morris EC, et al. HLA-mismatched
unrelated donors are a viable alternate graft source for alloge-
neic transplantation following alemtuzumab-based reduced-
intensity conditioning. Blood. 2010;115(25):5147-5153.
21. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with
standard-risk acute lymphoblastic leukemia, the greatest benefit
is achieved from a matched sibling allogeneic transplantation in
first complete remission, and an autologous transplantation is
less effective than conventional consolidation/maintenance
chemotherapy in all patients: final results of the International
236 American Society of Hematology

ALL Trial (MRCUKALLXII/ECOGE2993). Blood. 2008;111:
1827-1833.
22. Wassmann B Pfeifer H, BethgeW, Bornhauser J, et al. Up-front
versus minimal residual disease triggered imatinib after stem
cell transplantation for Philadelphia chromosome-positive acute
lymphoblastic leukaemia: interim results of a randomized phase
III GMALL study [Abstract]. Bone Marrow Transplant. 2009;
43:S48.
23. Burke MJ, Trotz B, Luo X, et al. Allo-hematopoietic cell
transplantation for Ph chromosome-positive ALL: impact of
imatinib on relapse and survival. Bone Marrow Transplant.
2009;43:107-113.
24. Ram R, Storb R, Sandmaier BM, et al. Nonmyeloablative
conditioning with allogeneic hematopoietic cell transplantation
for the treatment of high risk acute lymphoblastic leukemia.
Haematologica. 2011;96(8):1113-1120.
25. Preudhomme C, Henic N, Cazin B, et al. Good correlation
between RT-PCR analysis and relapse in Philadelphia (Ph1)-
positive acute lymphoblastic leukemia (ALL). Leukemia. 1997;
11:294-298.
26. Pane F, Cimino G, Izzo B, et al. Significant reduction of the
hybrid BCR/ABL transcripts after induction and consolidation
therapy is a powerful predictor of treatment response in adult
Philadelphia-positive acute lymphoblastic leukemia. Leukemia.
2005;19:628-635.
27. Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared
with chemotherapy as front-line treatment of elderly patients
with Philadelphia chromosome-positive acute lymphoblastic
leukemia (Ph!ALL). Cancer. 2007;109:2068-2076.
28. Lee S, Kim DW, Cho B, et al. Risk factors for adults with
Philadelphia-chromosome-positive acute lymphoblastic leukae-
mia in remission treated with allogeneic bone marrow transplan-
tation: the potential of real-time quantitative reverse-transcrip-
tion polymerase chain reaction. Br J Haematol. 2003;120:145-
153.
29. Yanada M, Sugiura I, Takeuchi J, et al. Prospective monitoring
ofBCR-ABL1transcript levels in patients with Philadelphia
chromosome-positive acute lymphoblastic leukaemia undergo-
ing imatinib-combined chemotherapy. Br J Haematol. 2008;
143(4):503-510.
30. Pfeifer H, Wassmann B, Pavlova A, et al. Kinase domain
mutations of BCR-ABL frequently precede imatinib-based
therapy and give rise to relapse in patients with de novo
Philadelphia-positive acute lymphoblastic leukemia (Ph!ALL).
Blood. 2007;110:727-734.
31. Soverini S, Vitale A, Poerio A, et al. Philadelphia-positive
acute lymphoblastic leukemia patients already harbor BCR-
ABL kinase domain mutations at low levels at the time of
diagnosis. Haematologica. 2011;96(4):552-557.
32. Bo¨hm A, Herrmann H, Mitterbauer-Hohendanner G, et al.
Stable non-transforming minimal residual disease in Philadel-
phia chromosome positive acute lymphoblastic leukemia after
autologous transplantation: origin from neoplastic yet ‘pre-
leukemic’ stem cells? Leuk Lymphoma. 2011;52(5):842-848.
33. Jones D, Thomas D, Yin CC, et al. Kinase domain point
mutations in Philadelphia chromosome-positive acute lympho-
blastic leukemia emerge after therapy with BCR-ABL kinase
inhibitors. Cancer. 2008;113:985-994.
34. Cortes J, Talpaz M, Bixby D, et al. A phase 1 trial of oral
ponatinib (AP24534) in patients with refractory chronic myelog-
enous leukemia (CML) and other hematologic malignancies:
emerging safety and clinical response findings [Abstract].
Blood. 2010;116:210.
35. Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with
the T-cell-engaging antibody blinatumomab of chemotherapy-
refractory minimal residual disease in B-lineage acute lympho-
blastic leukemia patients results in high response rate and
prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493-
2498.
36. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609
adults after relapse of acute lymphoblastic leukemia (ALL); an
MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-
950.
37. Ishida Y, Terasako K, Oshima K, et al. Dasatinib followed by
second allogeneic hematopoietic stem cell transplantation for
relapse of Philadelphia chromosome-positive acute lymphoblas-
tic leukemia after the first transplantation. Int J Hematol.
2010;92:542-546.
38. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus
concurrent schedules of imatinib and chemotherapy as front-
line therapy for Philadelphia-positive acute lymphoblastic
leukemia (Ph! ALL). Blood. 2006;108:1469-1477.
39. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib
combined with induction or consolidation chemotherapy in
patients with de novo Philadelphia chromosome-positive acute
lymphoblastic leukemia: results of the GRAAPH-2003 study.
Blood. 2007;109:1408-1413.
40. Ribera JM, Oriol A, Gonzalez M, et al. Concurrent intensive
chemotherapy and imatinib before and after stem cell transplan-
tation in newly diagnosed Philadelphia chromosome-positive
acute lymphoblastic leukemia. Final results of the CSTIBES02
trial. Haematologica. 2010;95(1):87-95.
41. Stein A, O’Donnell M, Snyder DS, et al. Reduced-intensity
stem cell transplantation for high-risk acute lymphoblastic
leukaemia. Biol Blood Marrow Transplant. 2009;15(11):1407-
1414.
42. Arnold R, Massenkeil G, Bornhauser M, et al. Nonmyeloabla-
tive stem cell transplantation in adults with high-risk ALL may
be effective in early but not in advanced disease. Leukemia.
2002;16:2423-2428.
43. Martino R, Giralt S, CaballeroMD, et al. Allogeneic hematopoi-
etic stem cell transplantation with reduced-intensity condition-
ing in acute lymphoblastic leukemia: a feasibility study.
Haematologica. 2003;88:555-560.
44. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity
conditioning allogeneic stem cell transplantation for adult
patients with acute lymphoblastic leukemia: a retrospective
study from the European Group for Blood and Marrow
Transplantation. Haematologica. 2008;93:303-306.
45. Bachanova V, Verneris MR, DeFor T, Brunstein CG,
Weisdorf DJ. Prolonged survival in adults with acute
lymphoblastic leukemia after reduced-intensity conditioning
with cord blood or sibling donor transplantation. Blood.
2009;113:2902-2905.
Hematology 2011 237