Blastic Phase of Chronic

Myelogenous Leukemia
Merat Karbasian Esfahani, MD*
Evelyn L. Morris, MD
Janice P. Dutcher, MD
Peter H. Wiernik, MD
Address
*Our Lady of Mercy Comprehensive Cancer Center, 600 East 233rd Street,
Bronx, NY 10466, USA.
E-mail: kar1070@yahoo.com
Current Treatment Options in Oncology 2006, 7:189–199
Current Science Inc. ISSN 1527–2729
Copyright © 2006 by Current Science Inc.

Opinion statement
Chronic myelogenous leukemia (CML), also known as chronic myelocytic or chronic myeloid
leukemia, is a clonal disorder of hematopoiesis that arises in a hematopoietic stem cell or
early progenitor cell. This is characterized by the dysregulated production of mature non-
lymphoid cells with normal differentiation. Eventually, in spite of the term chronic, there is
progression to acute leukemia, usually of the myeloid variety, which is highly resistant to
current therapies. Despite recent improvements in the treatment of early-stage disease,
CML blast crisis (CMLBC) remains a therapeutic challenge. CMLBC is highly refractory to
standard induction chemotherapy, with a response rate in myeloid blast crisis of less than
30%. Conventional chemotherapy has been much less successful in this disease compared
with de novo acute leukemia, with a mean survival after diagnosis of blast crisis of only
2 to 4 months for nonresponders. Many regimens of chemotherapies have been tried in
CMLBC, with minor success. Although imatinib was evaluated in patients with CMLBC, most
CMLBC cases today arise in patients already on imatinib-based therapy and developing
blastic phase on that therapy; thus there is no standard therapy for patients with CMLBC.
Further studies of the mechanisms of transformation of chronic-phase CMLBC at a molecu-
lar level, and methods to target these molecular abnormalities, will determine the future
direction of new treatment modalities. The prognosis of CML in blast crisis remains dis-
appointing, despite great efforts. Currently, the most successful strategy for improving
survival in CML is by prolonging the chronic phase and delaying the onset of blast crisis.

Introduction
Chronic myelogenous leukemia (CML) is a clonal dis-
order of hematopoiesis and a myeloproliferative stem
cell disorder, characterized by dysregulated production
and expansion of myeloid, erythroid, and megakaryo-
cytic cells. CML accounts for 15% of adult leukemias,
with an incidence of one to two cases per 100,000 pop-
ulation. Most patients present in their fifth and sixth
decades of life, with a male to female ratio of 1.3:1 [1•].
The disease is characterized by a biphasic or triphasic
course and the presence of a characteristic cytogenetic
abnormality, the Philadelphia chromosome (Ph) in
leukemic cells. Myeloid differentiation is not impaired
in CML, but hematopoietic stem cell behavior is abnor-
mal in tissue culture studies [1•,2]. CML progresses
from a chronic phase to an accelerated phase, followed
by a terminal blastic phase of lymphoid or myeloid
phenotype [3]. CML blast crisis (CMLBC) is highly
refractory to standard induction chemotherapy, with a
response rate in myeloid blast crisis of less than 30%.
Allogeneic stem cell transplantation during blast crisis
does not confer superior benefit, and the 5-year survival
rate is only 6%. Blast crisis is invariably fatal and despite
aggressive medical efforts, the median survival contin-
ues to be approximately 2 to 3 months [4,5]. Although
190 Chronic Leukemia
in the era of imatinib initial results in blast crisis were
promising [6•], ABL mutations in late chronic-phase
CML patients with upfront cytogenetic resistance to
imatinib are associated with a greater likelihood of pro-
gression to blast crisis and shorter survival [7]. Because
almost all chronic-phase patients are now treated with
imatinib, they are expected to be resistant when they
progress to blast crisis [7,8].
MOLECULAR GENETICS AND PHILADELPHIA CHROMOSOME
The Philadelphia chromosome (Ph), initially described
in 1960 [9], is present in more than 90% of individuals
with CML. The newly created BCR-ABL gene on the Ph
chromosome encodes a 210-kd chimeric protein, which
causes leukemogenesis and interferes with normal cell
cycle events, such as signal transduction and the regula-
tion of apoptosis and cell proliferation (p160 BCR and
p145 ABL) [10,11]. This aberrant protein has enhanced
tyrosine phosphokinase enzymatic activity and is
involved in the molecular pathogenesis of CML. The
normal ABL protein is found in the nucleus, where it
exerts its proapoptotic role, and in the cytoplasm.
In contrast, the BCR-ABL protein is exclusively cyto-
plasmic and is anti-apoptotic. BCR-ABL affects the
DNA repair process, and altered DNA repair leads to
genomic instability, which leads to clonal evolution
and progression to blast crisis [12]. Primitive Ph+
hematopoietic progenitors from patients with CML
show decreased adherence to bone marrow stroma [13]
and fibronectin [14] because of a defect in ␤-1 integrin
function, caused by the BCR-ABL protein. Although
BCR and C-ABL proteins have no intrinsic oncogenic
properties, the BCR-ABL protein has the ability to
transform cell lines and primary cells in vitro, behaving
as a classical oncogene [15].
BLAST TRANSFORMATION
Molecular biology Although the Ph chromosome trans-
location may be the initiating event in CML, progres-
sion to blast crisis appears to require the acquisition of
other chromosomal changes and/or dysregulation of
differentiation-regulatory genes [1•,16]. Although in
most cases there is a transition from an initial chronic
phase to an accelerated phase, and finally culmination
in an inevitable CMLBC, in 20% to 25% of patients,
the blastic phase develops without the intermediate
accelerated phase.
Several mechanisms have been implicated in the
malignant transformation produced by BCR-ABL, includ-
ing altered adhesion of hematopoietic cells to stroma
cells and extracellular matrix, activated signaling path-
ways that induce mitosis, inhibition of apoptosis, and
degradation of important cellular proteins [12]. It has
been postulated that the alleged anti-apoptotic effect
of BCR-ABL favors inaccurate DNA repair, whereas in
normal cells, DNA damage would induce apoptosis [17].
With progression of the disease, 50% to 75% of
patients acquire chromosomal changes in addition to
the Ph chromosome, and this may precede or accom-
pany hematologic and clinical manifestations of blastic
phase. The most frequently observed changes of karyo-
typic evolution are an additional Ph chromosome
(double Ph), isochromosome 17 (i17q), trisomy 8, and
trisomy 19 [1•]. Studies using fluorescent in situ
hybridization techniques are more sensitive in deter-
mining additional chromosomal abnormalities. Studies
have demonstrated new abnormalities in separate
subclones of blasts and in cases in which all lineages
demonstrate the abnormality.
Deletions and mutations of p53 occur in 20% to
30% of patients with CMLBC, associated with suppres-
sion of apoptosis [1•]. Amplification of c-myc is seen in
20% of patients. Other rare events observed include
mutations in ras and rearrangement and deletions of Rb
and p16. There is evidence to suggest that the biologic
abnormalities of CMLBC, namely the enhanced prolif-
eration and survival of cells and the arrest of differentia-
tion, are the consequence of abnormalities in the p53 or
Rb (or both) gene activity, or by dysregulation of differ-
entiation-regulatory genes (ie, C/EBP alpha) [16].
The enhanced leukemic potential of CML granulocyte
macrophage progenitor cells has also been attributed to
the activation of ␤-catenin, resulting in these progenitor
cells acquiring the capacity of self-renewal [18]. The ␤-
catenin levels in myeloid precursors in patients in blast
crisis are high and found to normalize once the patients
are treated with imatinib [17].
Some patients with CML demonstrate genomic
deletions resulting in loss of chromosome 9 and 22
sequences flanking the translocation breakpoint on the
derivative [9], on additional partner chromosomes, or
on both. Such deletions are associated with a worse
prognosis, with a median survival of 36 months (com-
pared with > 90 months in those without deletions),
and may influence the progression of CML [19].
Clinical manifestations At diagnosis of blast crisis, the
most common clinical symptoms are fatigue and mal-
aise. Other associated symptoms are fever, night sweats,
bone pain, weight loss, and bleeding and infection as
mature cells are depleted [1•]. Most of the patients have
progressive splenomegaly often leading to left upper
abdominal discomfort. Anemia is the most common
initial laboratory feature associated with progression to
accelerated or blastic phase. Thrombocytopenia, when
present at the onset of blast crisis, indicates a lower
degree of marrow reserve and has a negative influence
on patient survival. Increasing eosinophilia and/or
basophilia are signs of disease progression. Some
patients develop lymphadenopathy. Complications
associated with blast crisis include hyperleukocytosis,
leukostasis, bleeding, and infection. Radiation therapy
 Blastic Phase of Chronic Myelogenous Leukemia Karbasian Esfahani et al. 191

is used to manage leukostasis in the cerebral or pulmo-
nary vasculature, when the number of circulating blasts
is high. It is sometimes administered to control symp-
toms of splenomegaly and is the treatment of choice
for cranial nerve palsies from meningeal leukemia.
When the peripheral blast count is more than 100,000
cells/␮L, leukapheresis is indicated [20].
Chronic myelogenous leukemia blast crisis resem-
bles acute leukemia with an absence of mature cells and
is defined by the presence of extramedullary blastic
infiltrates, or of 30% or more leukemic blasts in the
peripheral blood and bone marrow [1•]. CMLBC is
highly resistant to therapy, with a median response
rate of only 20%, range 11% to 60% (Table 1). The
median survival in CMLBC is 2 to 3 months. Blast trans-
formation is most commonly myeloid [1•], but a lym-
phoblastic immunophenotype is seen in 20% to 30%
of cases. The blast transformation can even be mega-
karyocytic, and this is defined immunophenotypically.
Complete hematologic and complete marrow responses
were seen in 29% of 56 evaluable patients with relapsed
or refractory Ph+ acute lymphoblastic leukemia (ALL)
or CML in lymphoid blast crisis [21]. Because of respon-
siveness to vincristine and prednisone, lymphoid
blast crisis has a slightly better survival than does
myeloid blast crisis.

Treatment
Diet and lifestyle
• There is no evidence to support any role for diet and lifestyle changes in the
treatment of CMLBC.

Chemotherapy
• The treatment of CMLBC is a challenge because conventional chemotherapy
has been much less successful in this disease, compared with de novo acute
leukemia. The mean survival after diagnosis of blast crisis is only 2 to 4
months for nonresponders. In responders, standard chemotherapy yields
a response rate of approximately 30%. One-year survival for this group of
patients is 25%, but all of them eventually relapse with dismal prognosis.
Agents used in chronic phase, such as interferon and hydroxyurea, are ineffec-
tive in blast crisis. Table 1 summarizes various chemotherapy regimens that
have been used in treatment of CMLBC. The most commonly used induction
regimens have been a combination of an anthracycline (daunorubicin) or
anthracenedione (mitoxantrone) and cytarabine [22,23]. Mitoxantrone has
been used as a single agent or in combination, with some benefit [5,24].
Other agents in combination or as a single agent include 5-azacytidine, etopo-
side [4], carboplatin [24], cladribine [25], plicamycin, and hydroxyurea [26].
All-trans retinoic acid and arsenic trioxide, which has been used extensively
in acute promyelocytic leukemia, have been tried in CMLBC [27]. In 2002,
Bolaman et al. [5] reported a response rate of 54% in patients with CMLBC
using mitoxantrone, cytarabine, and high-dose methylprednisolone, but the
duration of response was short.
• Table 1 summarizes different chemotherapy treatments that have been evalu-
ated from 1982 to 2005. The response rates range from 11% to 77%, with
the median survival of responders ranging from 3.5 months to 19 months
[5,22–26,28–32], likely reflecting patient population or small numbers
treated. A few patients who responded to induction chemotherapy under-
went stem cell transplantation, with anecdotal reports of survivors.
• Approximately 30% of patients who develop CMLBC have a lymphoid
phenotype. In an evaluation of 97 consecutive patients with CMLBC,
patients with lymphoid CMLBC seldom had an accelerated phase before
blast crisis, had less frequent splenomegaly and hepatomegaly, and showed
a favorable response to chemotherapy regimens including vincristine and
prednisone [33]. However, remissions, if achieved, are generally very short.
In a series of 15 patients with extramedullary CMLBC, Specchia et al. [34]
Table 1. Available chemotherapy in blast crisis of CML (1982–present)
192

Median survival 1-year survival

Study Regimen Response rate Responders Nonresponders Responders Nonresponders

Schiffer et al. [28], n = 27 5-azacytidine/etoposide 58%; one CR, 7.7 months 2.5 months 20% 10%
15 PR
Koller and Miller [26], n = 9 Plicamycin/hydroxyurea 77%; seven CR 18 months NA NA NA
Kantarjian et al. [22], n = 27 Mitoxantrone/cytosine 30%; seven CR, 6 months 3 months 25% 8%
arabinoside one PR
Chronic Leukemia

Kantarjian et al. [23], n = 48 (CMLBC = 24) Daunorubicin/high-dose 33%; eight CHR 3.5 months 2 months 20% NA
cytosine arabinoside, GMCSF
Dutcher et al. [29], n = 40 Mitoxantrone/5-azacytidine 23%; five CR, 6+ months 3 months 37% 10%
two PR, two MR
Dutcher et al. [30]* (in accelerated phase), α-Interferon/plicamycin 30%; one CR, 5+ years 24 months 100%* 100%*
n = 13 (in accelerated phase) three PR
Dutcher et al. [31], n = 36 Carboplatin 22%; five CR, 12.8 months 3.5 months 50% NA
three PR
Robak and Gora-Tybor [25], n = 12 Mitoxantrone/cladribine 17%; zero CR, NA NA NA NA
two PR
Bolaman et al. [5], n = 14 Mitoxantrone/cytosine 64%; five CR, 19 months, CR; 2 months NA NA
arabinoside/high-dose four PR 14 months, PR
methyl prednisolone
Dutcher et al. [32], n = 18 All-trans retinoic acid 11%; one CR, 10 months 6 months 40% NA
one PR, three HI
Morris et al. [24], n = 20 Mitoxantrone/carboplatin 40%; five CR, 6.5 months 2 months 38% 17%
three PR
*This study was done in CML patients in accelerated phase.
CHR—complete hematologic response; CML—chronic myelogenous leukemia; CMLBC—chronic myelogenous leukemia blast crisis; CR—complete response; GMCSF—granulocyte-macrophage
colony-stimulating factor; HI—hematologic improvement; MR—major response; NA—not available; PR—partial response.
(Adapted from Morris and Dutcher [60••]; with permission.)
 Blastic Phase of Chronic Myelogenous Leukemia Karbasian Esfahani et al. 193

had a complete remission in all of the patients with lymphoid extramedul-

lary CMLBC using vincristine, daunorubicin, and prednisone. No single
regimen has emerged as a preferred treatment of CMLBC.

Allogeneic bone marrow transplantation

• Allogeneic bone marrow transplantation (BMT) is often considered the
only established “curative” therapy in chronic phase of CML [35••]. How-
ever, allogeneic BMT with a related or unrelated donor, a consideration
in patients with CMLBC, is usually unsuccessful in this later stage of the
disease, although the results report 10% to 20% of patients achieving long-
term disease-free survival. Transplantation in blastic phase is characterized
by an increased rate of leukemia relapses (80%) and treatment-related
mortality. Goldman et al. [36] in 1986 reported a series of patients with
CML who underwent allogeneic BMT. Two-year survival was 72%, with a
risk of relapse of 7% in patients treated in chronic phase, whereas patients
with more advanced disease had a 2-year survival of only 18%, with a
relapse rate of 42%. Fefer et al. [37], in a retrospective study, showed that
transplantation in CMLBC is associated with much lower long-term
survival (14%) in a follow-up time of 1 to 8 years, compared with patients
transplanted in chronic phase (58%).

Imatinib
• With the understanding that the consequence of the Philadelphia chromo-
some, translocation 9;22, was the formation of a unique gene product,
efforts were aimed at developing compounds that could selectively inhibit
the aberrant tyrosine kinase resulting from this molecular rearrangement.
Imatinib, which is a signal transduction inhibitor (STI), is a potent selective
competitive inhibitor of the BCR/ABL protein tyrosine kinase and is the
cornerstone of therapy in CML [38–41].
• Imatinib was developed by Lydon and Druker in collaboration with Ciba
Geigy (now Novartis Pharmaceuticals) in the early 1990s [42] and was first
administered to patients with CML in June 1998 [43]. It is orally adminis-
tered, with a bioavailability of almost 100%. It occupies the adenosine tri-
phosphate (ATP)-binding site of the ABL tyrosine kinase component of the
BCR-ABL oncoprotein and thereby prevents phosphorylation of any sub-
strate. It was designed to act by inhibiting the tyrosine kinase activity of
the BCR-ABL, but it was also found to inhibit the tyrosine kinases coded by
platelet-derived growth factor receptor (PDGF-r) and c-KIT (stem cell factor
receptor) [35••]. Although it is highly effective in the chronic phase of CML,
its role is less clear in CMLBC. Initially, the use of imatinib in these patients
generated hopes of better treatment options (Table 2). Patients with Ph1-
positive CML in blast crisis were treated with imatinib at doses ranging from
300 to 1000 mg/day. Druker et al. [6•] reported responses to imatinib among
58 treated patients with CMLBC. Although there was a higher response rate
among those with lymphoid blast crisis (70%), none remained in remission.
The response rate in myeloid blast crisis was 55%, with 50% having complete
hematologic responses (CHRs), and 36% of these responders remained in
remission for 3 to 12 months [6•]. None of these patients had received
imatinib in chronic phase.
• In a study by Kantarjian et al. [44], imatinib was used in patients with CMLBC
(65 patients with nonlymphoid blast crisis and 10 patients with lymphoid
blast crisis; they received 300–1000 mg daily of imatinib). Response rates
were similar between nonlymphoid and lymphoid groups (52%), with 16
Table 2. Imatinib in CMLBC
194

Cytogenetic Response duration, Median survival,

Study Daily dose, mg Response rate response rate months months 1-year survival

Druker et al. [6•], n = 588, 300–1000 Myeloid blast crisis: 55%, four CR; NA 3.3–11.6 NA NA
lymphoid = 20, myeloid = 39 lymphoid blast crisis/ALL: 70%,
four CR
Kantarjian et al. [44], n = 75, 300–1000 52%; 16 CR, three PR, no 16% NA 6.5 22%
lymphoid = 10, nonlymphoid = 65 difference lymphoid/nonlymphoid
Chronic Leukemia

Sawyers et al. [45], n = 260 400–600 52%, with 31% > 4 weeks; CHR 8% 7% 10 6.9 (7.3 for 600 mg) 32%
Sureda et al. [40], n = 30 600 60% > 4 weeks 8% 5 NA 36% ± 13%
Zhang et al. [46], n = 19 400/600 + 57%; six CR, two PR NA NA NA 38%
cytarabine
ALL—acute lymphoblastic leukemia; CHR—complete hematologic response; CMLBC—chronic myelogenous leukemia blast crisis; CR—complete response; NA—not available;
PR—partial response.
(From Morris and Dutcher [60••]; with permission.)
Blastic Phase of Chronic Myelogenous Leukemia Karbasian Esfahani et al. 195

complete and three partial hematologic responses; 12 had hematologic

improvement, and seven returned to chronic phase. The overall median sur-
vival was 6.5 months, and the 1-year survival was 22%.
• Concurrently, during a phase II trial of imatinib in CMLBC, Sawyers et al.
[45] evaluated 229 patients. The hematologic response was 52%, with a
sustained response of 31% (beyond 4 weeks with median of 10 months).
CHRs were reported in 8% of patients, with major cytogenetic responses
(CyRs) in 16% and complete CyRs in 7%. The median survival of all
treated patients was 6.9 months. Using imatinib with a higher dosage of
600 mg daily appeared to produce a longer median survival (7.3 months),
compared with 4.5 months with 400 mg daily.
• Other smaller series have been reported with response rates of 57% to 60%
using different dosages of imatinib (Table 2). Sureda et al. [40] reported 18
of 30 (60%) patients achieving sustained hematologic response (> 4 weeks),
with a median duration of 5 months. They observed a better response to
higher doses of imatinib. Also, the presence of a complex karyotype and/or a
long time interval between the diagnosis of the blast crisis and the institution
of imatinib therapy significantly worsened the overall survival and event-free
survival of patients [40].
• In a study by Zhang et al. [46], 19 patients were treated with imatinib
400 mg/day plus standard cytarabine-based chemotherapy. After 4 weeks,
if no remission was obtained, imatinib was increased to 600 mg/day for
another 8 weeks. Induction chemotherapy could not achieve a remission
in most patients (16/19), but prolonged high-dose imatinib produced a
complete remission in six of 16 patients. Also, two patients had partial
remissions and one returned to the chronic phase, with 1-year survival of
38% in responding patients.
• Side effects of imatinib include myelosuppression and toxicities observed
with its use in chronic phase. Reports have shown that significant progres-
sion of marrow reticulin fibrosis during imatinib therapy can be an indica-
tor for progression of CML [27]. Also, imatinib may promote cytogenetic
clonal evolution, resulting in a poor response to treatment [27]. Resistance
also has been described [47]. Pfeifer et al. [48] reported three patients with
CML who rapidly progressed from chronic phase to blast crisis while taking
imatinib for 7 to 10 months. Increased frequency of extramedullary blast
crisis, including central nervous system relapse, has been reported [48,49].
Imatinib has a limited ability to penetrate the intact blood-brain barrier [50]
and thus may not be sufficient therapy for patients in blast crisis with central
nervous system involvement [49]. Drug resistance has been associated with
molecular or cytogenetic causes such as reactivation of Bcr/Abl signal trans-
duction, amino acid substitutions that changed the conformation of the
ATP-binding site, and additional chromosomal aberrations [51].
• Relapses of imatinib-treated chronic phase patients have demonstrated new
clinical patterns, including patients with complete CyR who have abruptly
developed blast crisis, suggesting that mechanisms additional to BCR-ABL
are important in the transition to blast crisis [49,52].
• At present, the role of imatinib in patients in blast crisis is not clear,
particularly because many have now received imatinib in chronic phase.
Most patients with CMLBC who respond will relapse relatively quickly
[10]. Nevertheless, imatinib provides a less toxic induction therapy and
is associated with fewer deaths during induction [44]. In vitro culture
studies have indicated that CD34+ CML progenitor cells can remain
viable in a quiescent state in the presence of imatinib and growth factors.
These cells could be responsible for resistance or relapse during treatment
with imatinib or after cessation of imatinib therapy [53]. To overcome
196 Chronic Leukemia

Table 3. Dasatinib in CMLBC and accelerated phase

Study Dosage Response rate Cytogenetic response

Talpaz and Rousselot [55•], n = 74 70 mg orally twice daily (dose 55% MHR, 24% CHR 45%, with 21% CR and 17% PR
escalation: 100 mg orally twice
daily; dose reduction: 50 and
40 mg orally twice daily)
Guilhot et al. [56•], n = 35 70 mg orally twice daily (dose 66% MHR, 20% CHR 54%, with four of 24 complete
escalation: 100 mg orally twice CyR (0% Ph+) and two of 24
daily; dose reduction: 50 and partial CyR (1% to 35% Ph+)
40 mg orally twice daily)
CHR—complete hematologic response; CMLBC—chronic myelogenous leukemia blast crisis; CR—complete response; CyR—cytogenetic
response; MHR—major hematologic response; Ph—Philadelphia chromosome; PR—partial response.

resistance to imatinib, several approaches have been studied, including

escalation of the dose of imatinib and the combination of imatinib with
chemotherapeutic drugs [54].

Dasatinib
• Dasatinib (BMS-354825) is an oral multitargeted kinase inhibitor, which
targets BCR-ABL and SRC kinases. Talpaz and Rousselot [55•] conducted
a phase II trial with dasatinib in myeloid CMLBC. Seventy-four imatinib-
resistant (IM-R) or intolerant (IM-I) patients participated. The preliminary
data were reported for 29 IM-R and five IM-I patients. Median age of the
patients was 54 years (71% male and 29% female), and median duration of
CML from first diagnosis was 49.3 months. In 44% of patients, the highest
dose of imatinib was 600 mg/day, and 41% of patients received imatinib
for more than 3 years, with CHR in 82% of patients. Other prior treatments
included BMT and interferon. Dasatinib was administered at the dosage of
70 mg orally twice daily, with dose escalation to 100 mg orally twice daily
(in 32% of patients) or dose reduction to 50 mg and 40 mg orally twice
daily in some patients based on the hematologic response or persistent
toxicity. The results were as follows: major hematologic response was 16/29
(55%), with seven CHRs; nine patients had no evidence of leukemia; 13
patients (45%) showed CyR, including six (21%) complete (0% Ph+) and
five (17%) partial responses (1% to 35% Ph+) [55•]. A full report on the
74 patients is awaited with interest (Table 3).
• Dasatinib also has been used in patients with accelerated-phase CML who
are resistant or intolerant to imatinib (Table 3). In a phase II study, prelim-
inary results were reported on 35 patients, using the earlier-mentioned
dosages in the study by Talpaz and Rousselot [55•]. Major hematologic
response was reported in 23 patients (66%), with seven CHRs and 16
patients with no evidence of leukemia. In addition, CyR was seen in 13/24
patients (54%), with four complete CyRs and two partial CyRs [56•]. Side
effects of dasatinib include profound myelosuppression. Nonhematologic
toxicities were uncommon.
• These data suggest that dasatinib has potent activity with high hematologic
and CyR rates in myeloid CMLBC and CML accelerated phase in patients
who are resistant or intolerant to imatinib (Table 3). Further clinical evalu-
ation and understanding of molecular pathways for overcoming resistance
is currently underway.
 Blastic Phase of Chronic Myelogenous Leukemia Karbasian Esfahani et al. 197

Emerging therapies
• Parthenolide, a naturally occurring small molecule, induces robust apoptosis
in primary human acute myelocytic leukemia cells and CMLBC cells, while
sparing normal hematopoietic cells. The activity of parthenolide triggers
leukemia stem cell (LSC)-specific apoptosis and as such may represent a
potentially important new class of drugs for LSC-targeted therapy [57].
• Recent studies by Yu et al. [58] and Dai et al. [59] examined the interaction
between bortezomib, a proteosome inhibitor, and histone deacetylase
inhibitors in BCR-ABL (+) human leukemia cells and have demonstrated
synergistic anti-leukemic activity. There was an increase in mitochondrial
injury, caspase activation, and apoptosis. This was evident even in apoptosis-
resistant cell lines. These data also can be viewed as an efficient way to treat
CMLBC. Clinical evaluation is ongoing.

Future directions
• Further studies of the mechanisms of transformation of chronic phase
CMLBC at a molecular level, and methods to target these molecular abnor-
malities, will determine the future direction of new treatment modalities.
Different chemotherapy agents and STIs have been tried. The prognosis of
CML in blast crisis remains disappointing, despite these efforts. Currently,
the most successful strategy for improving survival in CML is by prolonging
the chronic phase and delaying the onset of blast crisis. Nevertheless, there
is considerable enthusiasm that further understanding of the molecular
events may lead to additional targeted approaches to then prevent the
transformation to CMLBC. Imatinib and subsequently dasatinib trial
results have been promising in treating the CMLBC. In the interim, clinical
trials in CMLBC using agents that may induce a return to chronic phase
continue to be important.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as:
• Of importance
•• Of major importance
1.• Faderl S, Talpaz M, Estrov Z, et al.: Chronic myelogenous
leukemia: biology and therapy. Ann Intern Med 1999,
131:207–219; and The biology of chronic myeloid
leukemia. N Engl J Med 1999, 341:164.
This study provides a useful overview of switching treatment
of CML from chemotherapy to targeted therapy based on the
biology of the disease.
2. Deininger MW, Goldman JM, Melo JV: The molecular
biology of chronic myeloid leukemia. Blood 2000,
96:3343–3356.
3. Giles FJ, Cortes JE, Kantarjian HM, et al.: Accelerated
and blastic phases of chronic myelogenous leukemia.
Hematol Oncol Clin North Am 2004, 18:753–774.
4. Axdorph U, Stenke L, Grimfors G, et al.: Intensive
chemotherapy in patients with chronic myelogenous
leukemia (CML) in accelerated or blastic phase--a
report from the Swedish CML group. Br J Haematol
2002, 118:1048–1054.
5. Bolaman Z, Koseoglu M, Ayyildiz O, et al.: Treatment of
blastic phase chronic myeloid leukemia with mitox-
antrone, cytosine arabinoside and high dose methyl-
prednisolone. Hematologica 2002, 32:49–57.
6.• Druker BJ, Sawyers CL, Kantarjian HM, et al.: Activity of
a specific inhibitor of the BCR-ABL tyrosine kinase
in the blast crisis of chronic myeloid leukemia and
acute lymphoblastic leukemia with the Philadelphia
chromosome. N Engl J Med 2001, 344:1038–1042.
This pilot study is one of the pioneer studies that evaluated the
effect of tyrosine kinase inhibition in patients with CMLBC
and Ph-positive ALL.
7. Soverini S, Martinelli G, Rosti G, et al.: ABL mutations
in late chronic phase chronic myeloid leukemia
patients with up-front cytogenetic resistance to ima-
tinib are associated with a greater likelihood of pro-
gression to blast crisis and shorter survival: a study
by the GIMEMA Working Party on Chronic Myeloid
Leukemia. J Clin Oncol 2005, 23:4100–4109.
198 Chronic Leukemia
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