Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

How has treatment changed for blast phase

chronic myeloid leukemia patients in the tyrosine
kinase inhibitor era? A review of efficacy and
safety

Salvatore Perrone, Fulvio Massaro, Giuliana Alimena & Massimo Breccia

To cite this article: Salvatore Perrone, Fulvio Massaro, Giuliana Alimena & Massimo Breccia
(2016): How has treatment changed for blast phase chronic myeloid leukemia patients
in the tyrosine kinase inhibitor era? A review of efficacy and safety, Expert Opinion on
Pharmacotherapy, DOI: 10.1080/14656566.2016.1190335

To link to this article: http://dx.doi.org/10.1080/14656566.2016.1190335

Accepted author version posted online: 27

May 2016.
Published online: 27 May 2016.

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 Publisher: Taylor & Francis

Journal: Expert Opinion on Pharmacotherapy

DOI: 10.1080/14656566.2016.1190335
Review

How has treatment changed for blast phase chronic myeloid leukemia
patients in the tyrosine kinase inhibitor era? A review of efficacy and
safety

Salvatore Perrone1, Fulvio Massaro1, Giuliana Alimena1 and Massimo Breccia1

Downloaded by [University of Otago] at 04:56 03 June 2016

1
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University,
Rome, Italy

Corresponding author:
Massimo Breccia, MD
Department of Cellular Biotechnologies and Hematology
Sapienza University
Via Benevento 6, 00161 Rome, Italy
Tel. 003906857951
Fax 00390644241984
e-mail: breccia@bce.uniroma1.it

Declaration of interest

M Breccia received honoraria from Novartis, Bristol, Pfizer and Ariad. The authors have no other
relevant affiliations or financial involvement with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials discussed in the manuscript apart from
those disclosed

1
 Abstract

Introduction. Management of chronic myeloid leukemia (CML) patients in advanced phases of

disease has drastically changed since the introduction of tyrosine kinase inhibitors (TKIs) which
provide tailored treatment strategies.

Areas covered. In this review, efficacy data of different TKIs are reported and reviewed when used
as single agent or in combination for the management of blast phase (BP) CML.

Expert Opinion. Although brilliant results were achieved, the outcome of BP patients did not
change when TKIs were used as single agents. Newer strategies of association of TKI with
intensified chemotherapy or new agents for different pathways are strongly needed as a bridge to
possible allogeneic transplant.
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Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, blast phase, outcome

Article highlight Box

1. TKIs in chronic phase CML have drastically reduced evolution to blastic phase.

2. TKIs allow achievement of transient haematological and cytogenetic responses in BP-CML as

bridge to HSCT.

3. TKIs combined with chemotherapy can achieve molecular remissions, but toxicity is higher.

4. No randomized clinical trials compared results of these therapeutic strategies.

5. Investigational agents not targeting ABL1 are strongly needed in BP CM

2
 1. Introduction

Blast phase (BP) represented the terminal phase of natural history in chronic myeloid leukemia
(CML), in particular in the pre-imatinib era. The BP can be either myeloid or lymphoid and current
WHO definition proposes a blast count e 20%, analogous to the definition of AML while the
European LeukemiaNet proposes a marrow blast count e 30%1. The clinical setting is
characterized by presence of fever, night sweats, bone pain, weight loss, cytopenia or extreme
leukocytosis, lymphadenopathy, hepatosplenomegaly, and extramedullary disease. Moreover,
some patients, as reported in a large registry-based cohort with an incidence of 2.2%, have already
developed a BP at their initial diagnosis 2; those cases are difficult to be differentiated between de
novo Ph-positive acute lymphoblastic leukemia (ALL) or acute myeloid leukaemia (AML).
Fortunately, the introduction and the widespread treatment with BCR-ABL tyrosine kinase inhibitors
(TKIs) have dramatically reduced the occurrence of this complication. In fact, in trials testing the
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effects of TKI in chronic phase CML patients the incidence of BP is between 1%, considering only
3,
patients in treatment with second-generation TKIs, to 8% in the long-term treatment with imatinib
4
. The biologic basis of the progression from chronic phase through accelerated phase to blast
crisis is poorly understood and involves BCR/ABL1 mutations and gain of new gene expression
5, 6
changes . Currently, BP is treated with any of the approved TKI (imatinib, dasatinib, ponatinib,
bosutinib with exception of nilotinib that is not available with this indication) alone or in combination
with intensive chemotherapy or with novel agents. However, responses are of short duration and
prognosis remains severe, thus a consolidation with allogeneic stem cell transplantation (HSCT) is
recommended by ELN guidelines 1. This review will cover the efficacy and safety of available
treatment for BP CML.

2. Historical treatment of BP CML

During the 1960s various attempts of treatment of BP in CML were translated from acute myeloid
leukemia (AML) regimens. At the beginnings of the ‘70s was noted that drugs effective in acute
lymphoblastic leukemia (ALL) could induce transient response in BP. Therein, vincristine (2 mg/m2)
and prednisone (60 mg/m2) resulted in a response in 30% of treated patients with BP 7. Later, it
was ascertained that BP with TdT+ cells (lymphoid BP) were sensitive to drugs active in ALL, like
vincristine 8. Those findings justify the current use of flow-cytometry to discern between myeloid
and lymphoid BP and their different management. Later, in the ‘80s and ‘90s, several AML-type
9, 10
induction therapies were tested (alone and also in combinations): anthracyclines , cytarabine 11,
etoposide 12, 13, carboplatin 14.

There are data suggesting that epigenetic anomalies are associated with CML progression and
15-17
provide a rationale for reassessing the use of demethylating agents in myeloid BP CML .

3
 Therefore, hypomethylating agents, especially in elderly patients with BP CML, have a role with 5-
azacytidine and decitabine 11, 13, 18, 19.

3. TKIs in BP CML

Inhibition of kinase activity of fusion protein BCR/ABL1 represents the mainstream of the treatment
for chronic phase CML. However some patients develop (or resistant clones emerge by the
selective pressure of the drug) mutation in BCR/ABL1 conferring a resistance to TKIs. On the other
hand, in BP-CML several others mechanisms not involving BCR-ABL1 deregulation are frequently
involved and might have a causative role in disease progression: genomic instability usually results
from an aberrant cellular response to enhanced DNA damage; defects in centrosome system;
20, 21
telomere shortening and inappropriate telomerase activation . Moreover, P53 mutations are
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frequently found in later phases of CML22. In particular, a deep sequencing study detected
additional mutations in about 75% of patients and a high mutation rate in several genes like RUNX,
23
ASXL1 and IKZF1, which represents important mechanisms in the progression of CML . ELN
panel has suggested different approach for the treatment of BP in 2013: for newly diagnosed BP
naïve patients, imatinib 800 mg or dasatinib 140 mg, with allogeneic bone marrow transplant
recommended for patients who did not reach an optimal response (previous chemotherapy to
control disease); for patients who progressed to BP after a previous TKI treatment, anyone of the
TKIs not used before progression then allogeneic transplant1.

3.1 Imatinib

In 2001 was published the first report on the phase I results of the former named STI571, imatinib
24, 25
mesylate given at progressive doses from 300 to 1000 mg . This study enrolled 58 patients, 38
had CML in myeloid BP, 10 had CML in lymphoid BP, and 10 had ALL-Ph+. Hematologic
responses, defined as <15% bone marrow blasts, were observed in 59% of patients in myeloid BP,
with complete disappearance of blasts in 33% of patients. In lymphoid BP, 70% of patients
24
responded and in 55% blasts disappeared . Nevertheless, responses were short lived; in myeloid
BP only 20% of the responders remained leukemia-free at 1-year while in lymphoid BP all patients
relapsed between 45 and 120 days.
In a phase II study imatinib, given at doses of 400 or 600 mg, was tested in 229 patients with
26
diagnosis of myeloid BP CML . Of these, 119 (52%) obtained a haematological response: in
particular, there were 35 (15%) complete hematologic remission (CHR). Major cytogenetic
responses (MCyR) were reported in 37 patients (16%) and 7% of those responses were complete.
The estimated median duration of response was 10 months (95% CI, 7.2-12.6 months), and 68%
out of 70 responding patients had a response exceeding 6 months. The estimated median OS was
6.9 months (95% CI, 5.7-8.7 months) and OS was 32% at 1 year. Profile of toxicity was similar to

4
 what described in the phase I study and in particular serious adverse events related to treatment
were reported for 47 patients (18%) and were most frequently hematologic events, including
neutropenia, thrombocytopenia, and febrile neutropenia. Data from an extended follow-up of 48
months, showed that only 3% of patients remained on imatinib therapy. The primary reasons for
discontinuation were progression or lack of efficacy (69.0%), protocol violations (6.3%), adverse
events or toxicity (8.5%), bone marrow transplant (4.5%), and death (11.7%) 27.
A single institution study performed at MD Anderson Cancer Center enrolled 75 patients in BP (65
myeloid and 10 lymphoid). Patients were treated with imatinib at doses ranging between 300-1000
mg. Briefly, the objective response rate was 52%, and the cytogenetic response rate was 16% with
an estimated median survival of 6.5 months. Interestingly, results of imatinib and historical results
of cytarabine-containing regimens were compared: 55 % of CHR was seen in the imatinib mesylate
group and 29% in the cytarabine group (P = .001). The 4-week mortality rates were 4% in the
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imatinib mesylate group and 15% in the cytarabine group (P = .07). Survival was longer among
patients treated with imatinib mesylate than those treated with cytarabine regimens (median
survival, 7 months versus 4 months, P = .04; 1-year survival rates, 23% versus 15%) 28.
An Italian (GIMEMA) phase II trial on 92 BP CML (72 myeloid and 20 lymphoid) patients imatinib-
naïve was concluded with a long 6-year follow-up. At a fixed dose of imatinib 600mg, 46 patients
(50%) returned to chronic phase, and 24 patients (26%) obtained a CHR. After a median duration
of response of 11 months (range, 1-67) the morphological response achieved, was unfortunately
29
subsequently lost by 22 patients. Sixteen patients (17%) had a cytogenetic response . The
median survival time of all patients was 7 months. After a median follow-up of more than 5 years,
only 7% of the study population were still alive.

For imatinib a long follow-up of patients treated in several studies is available. Imatinib have limited
toxicity but in BP-CML more myelosuppression than in chronic phase is reported due to limited
marrow reserves. Imatinib single agent is effective to induce rapid responses in BP-CML with
reported CHR ranging between 55 and 34%. Unfortunately, the response to imatinib is transient
and this is reflected in a median survival of 7 months in the different trials. This survival does not
differ from historical treatment with conventional chemotherapy agents. Only a small minority of
patients are long-term survivors from BP and it justify only the use of imatinib as a bridge to
transplant that can induce a durable remission in less than 10% of patients and an OS at 2 years
30
ranging from 16% to 22% . Given that the median time to find an unrelated donor is 3.5
31
months , all patients eligible for allogeneic stem cell transplantation should search a donor as
soon as possible after the diagnosis of BP.

3.2 Dasatinib

Dasatinib is a 2nd generation TKI that differs from imatinib due to its ability to bind to both active
and inactive conformations of the ABL, its in vitro activity of 325 times greater than imatinib and

5
 32, 33
that it can also binds SRC family of kinases . Dasatinib is effective against wild-type and
various mutant forms of BCR-ABL1 mutations except T315I 34. Limited to the setting of CP-CML, in
the DASISION study dasatinib induced significantly higher and faster rates of CCyR and major
35, 36
molecular response than imatinib . Therefore, dasatinib was also tested in more advanced
phases of CML, where faster and deeper response could have been beneficial.
A Phase I study of dasatinib was open to the different phases of CML, thus including 23 with
myeloid BP, and 10 with lymphoid BP or Ph-positive ALL. In myeloid BP, 8 patients (35%) had a
CHR and 8 (35) had a MCyR, while in lymphoid BP 7 patients (70%) had a CHR and 8 (80%) had
a MCyR. However, all (except one) of the patients with lymphoid BP or Ph-positive ALL had a
relapse after a median of only 4 months and in myeloid BP only 6 of 14 patients (43 %) who
reached a MHR were still on drug after a follow-up ranging from 5 to 12 months 37.
A Phase 2 START program (SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of
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dasatinib) tested dasatinib 140 mg/day in 109 (myeloid) and 48 (lymphoid) BP CML patients who
had been previously treated with imatinib (resistant/intolerant). CHR was obtained in 25% and 29%
of patients and MCyR was attained by 33 and 52% of patients, in myeloid and lymphoid BP
respectively. Median PFS was 6.7 (95% CI, 3.5–10.2) months, and 3.0 (95% CI, 2.3–5.0) months
and median OS was 11.8 months (95% CI, 7.1–no upper bound), and 5.3 months (95% CI, 4.0–
11.4) in patients with myeloid and lymphoid BP CML, respectively 38, 39.
A further Phase III study compared dasatinib given at 70 mg BID vs. 140 QD in 214 patients with
40
CML, 149 myeloid and 61 lymphoid . Not surprisingly, the results of the two equivalent regimens
were similar. CHR was seen in 17% of patients and CCyR in 14% for the once-daily regimen and
21% in the refracted doses. The median OS was about 7 months with and a 24-month OS of 24%
in myeloid BP. Among the patients with lymphoid BP, the median OS also was 11 months. Grade 1
and non-haematological toxicities were fluid retention, diarrhoea, headache, bleeding, nausea,
fatigue, and rash while the most important grade 3-4 event was pleural effusions occurred less
frequently on the once-daily regimen (21%). Cytopenias were common and 79% of patients had
neutropenia and 81% thrombocytopenia 40.
The results showed clearly that dasatinib was effective in BP-CML, but OS did not increase. Since
a RCT comparing results with imatinib was never performed, clear evidence of dasatinib over
imatinib cannot be inferred and the choice should consider more potential toxicity and increased
costs of dasatinib. However, results of dasatinib might be better if used in first line in BP-CML.

3.3 Nilotinib
Nilotinib is a 2nd generation TKI designed against BCR-ABL1 with an in vitro activity 30 times
32
greater than imatinib . It inhibits most imatinib-resistant BCR-ABL forms, but it is not active
against T315I mutant clones and inhibits c-KIT, PDGFR, the ABL-related kinase ARG, DDR1

6
 kinase and the oxidoreductase NQO2 but does not inhibits Src family members like dasatinib
does 41. Nilotinib was tested in BP CML even if it is not registered for this indication.
In a phase I study a dose finding of nilotinib was performed at 50 mg, 100 mg, 200 mg, 400 mg,
600 mg, 800 mg, and 1200 mg QD and 400 mg BID and 600 mg BID. Thirty-three patients had BP,
13 had a hematologic response to nilotinib (39 %) and 6 patients had a MCyR 42.
Another study was performed in 136 patients previously imatinib-treated who developed a BP CML
nilotinib was given at 400mg BID. A CHR was obtained in 24% with myeloid and 21% with
lymphoid BP CML patients. A CCyR was obtained in 30% with myeloid and in 32% with lymphoid
BP CML patients. The median OS was 10.1 months for patients with myeloid BP and 7.9 months
for patients with lymphoid BP, corresponding to 12- and 24-month survival rates of 42% and 27%,
respectively. The majority of patients developed cytopenias and the most common drug-related
adverse events were rash, nausea, diarrhoea and vomiting.43
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Results of an expanded access, multinational phase IIIb study (Expanding Nilotinib Access in
44
Clinical Trials [ENACT]) showed result of nilotinib in AP and BP CML outside a clinical trial . In
this article 190, imatinib-resistant or -intolerant, patients with BP-CML (133 myeloid and 50
lymphoid) were treated with nilotinib 400 mg BID. Nilotinib therapy resulted in CHR in 8.4% of
patients with BP-CML (myeloid 6.8% and lymphoid 14.0%). Moreover, 12.6% achieved a CCyR
(myeloid 8.3% and lymphoid 26.0%). At 18 months, the estimated OS was 63% (95% CI: 51 –
72%) for the BP-CML population 44.

3.4 Bosutinib
Bosutinib is a 2nd TKI that inhibits both BCR-ABL1 and SRC kinases, but with minimal activity
against KIT and PDGFR, which is thought to contribute to its peculiar therapeutic and safety
profile 45. An interim analysis of a phase I/II study was recently published of 88 patients in BP CML
(64 had a myeloid BP and 24 had an ALL Ph+) treated with bosutinib 500-600 mg. All patients had
already received imatinib and half of them were also been treated with another 2nd generation TKI.
Among 60 evaluable patients with BP CML, a confirmed overall hematologic response (OHR) was
newly attained/maintained by 17 (28%) patients with 10 (17%) with a CHR by week 48. Among 50
patients without a CCyR at baseline, 11 (22%) achieved a CCyR by 4 years and all four patients
with a CCyR at baseline maintained a CCyR on bosutinib. In patients with myeloid BP CML the
median OS duration was of 10.9 (8.7–19.7) months; the estimated OS was 42% and 23% at 1 year
and 4 years, respectively. The most common treatment-emergent adverse events occurring in
more 30% of all advanced leukemia patients were gastrointestinal, including diarrhea (74%),
nausea (48%) and vomiting (44%). Other AEs were thrombocytopenia, anemia, pyrexia and
rash 46.

7
 3.5 Ponatinib

Ponatinib is a potent 3rd generation TKI with substantial activity including threonine-to-isoleucine
25, 33, 37,
mutation at codon 315 (T315I) that confers resistance to all other approved BCR-ABL TKIs
42, 47-49
. Amino acid T315 is also known as the gatekeeper since its location to the periphery of the
50
nucleotide-binding site of ABL1 . Ponatinib was specifically developed through a structure-guided
drug-design strategy targeting the inactive conformation of the ABL1 kinase and avoiding the steric
51
hindrance of the side chain of 315I . The presence of mutation T315I is more frequent in more
52
advanced phases of CML . For those reasons, ponatinib may be beneficial in the setting of BP
CML and search for this mutation by Sanger analysis is generally advised 53.
In a phase I study ponatinib was tested in 65 patients with haematologic cancer of these 8 with BP
CML and 5 with ALL. It showed substantial activity in Ph+ patients and toxicity mainly consisted of
pancreatitis, skin disorders, constitutional symptoms and myelosuppression 54.
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In the subsequent phase II study on ponatinib, 62 patients had a BP-CML. Of these, 31% had a
major hematologic response and 23% had a major cytogenetic response. Other 32 patients had
Ph-positive ALL and 41% (95% CI, 24 to 59) had a major hematologic response, 47% had a major
cytogenetic response and 38% had a complete cytogenetic response. At 12 months PFS was 19%
(median, 4 months), and in patients with Ph-positive ALL, the PFS was 7% (median, 3 months).
The overall survival rate at 12 months was 29% (median, 7 months) in patients with blast-phase
CML and 40% (median, 8 months) in Ph-positive ALL patients. The most frequently observed
toxicities were rash (34% of the patients), dry skin (32%) and abdominal pain (22%). Their severity
was grade 1 or 2. Main hematologic toxicities were thrombocytopenia (37% of patients),
neutropenia (19%), and anaemia (13%). Arterial thrombotic events were observed. Moreover were
reported cardiovascular (2.2%), cerebrovascular (0.7%), and peripheral vascular (1.6%) events
possibly related to treatment 55At last ASH 2015, Nicolini presented an interesting study comparing
results from interpoled data from patients treated with ponatinib or with allogeneic SCT (from
EBMT database). Among patients with BP-CML, ponatinib was associated with significantly shorter
OS compared with allogeneic SCT: median 7.0 vs. 10.5 months (p=0.026), HR=2.29 (95% CI:
56
1.08, 4.82, p=0.030) . Even if better results are obtained with SCT than with ponatinb, we
underline that it is not a randomised trial.

4. TKIs in combination

As discussed in the previous paragraph (TABLE 1), results of TKIs alone in BP-CML are quite
57
unsatisfactory, probably due to their inability to eradicate the leukemic clone and rapid onset of
58, 59
BCR-ABL1 mutations that confer resistance to TKI monotherapy . Therefore, attempts to
combine TKI in a backbone of standard cytotoxic agents (also incorporating other investigational
agents) have been performed 60.

8
 The rationale behind these combinations encompasses: agents in combination may overcome
resistance of leukemia cells to single TKI, reducing clonal selection of resistant leukemia cells;
response is more rapid allowing a faster consolidation with HSCT sooner; deeper molecular
response may allow leukemic stem cells eradication. However, combination schedules are
expected to be more toxic and possibly not feasible in the setting of elderly, unfit patients.

In a pilot study, 31 patients with resistant Ph+ ALL (18) or lymphoid BP CML (13) were treated with
imatinib 400mg BID plus a chemotherapy induction with weekly vincristine 2 mg and
dexamethasone 40mg (DIV regimen: Dexamethasone, Imatinib and Vincristine). Of these 13 with
lymphoid BP CML 11 had a CHR (84%) and 6 obtained a CCyR. Infections were documented in
61
32% . In a recent study from MD Anderson 42 patients with lymphoid BP CML were treated with
Hyper-CVAD and imatinib (27) or dasatinib (15) between 2001 and 2011. CHR was achieved in
62
90% of patients, CCyR in 58%, and complete molecular remission in 25% . Median OS was 17
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months (range, 7-27 months). All patients experienced grade 3 or 4 neutropenia and
thrombocytopenia during treatment, and 88% of them had anaemia, 59% had infections and only 3
62
patients completed the planned 8 cycles . Toxicity of Hyper-CVAD + imatinib or dasatinib
appears to be too toxic for elderly patients. Similar results were reported in previous studies 63-65.

At MD Anderson 19 patients with myeloid BP-CML, received imatinib 600 mg plus cytarabine 10
mg/day subcutaneous, and idarubicin 12 mg/m2 every two weeks. Nine patients achieved a CHR
66
(47%), 3 with CCyR. The median OS was 23 weeks with 26% alive at 1-year . In a phase I study
imatinib 600 mg was combined with cytarabine at 200 mg/d for 7 days, with escalating doses of
daunorubicin for 3 days. Of the 36 patients with myeloid BP-CML treated with 3+7 regimen plus
imatinib, 55.5% had a CHR and 30.5% a CCyR. The median OS was 16 months, while for patients
in CHR it was 35.4 months. The median duration of grade 3–4 neutropenia and thrombocytopenia
67
were 24 and 27 days respectively and 13 patients presented infections . In a small British study,
4 patients with myeloid BP-CML were treated with dasatinib and a conventional scheme of
chemotherapy: FLAG-IDA. All patients achieve a CHR and CCyR and 3 also a major molecular
68
response . In a phase II study 10 patients with myeloid BP CML were treated with an association
of imatinib 600 mg and decitabine at 15 mg/m2 daily intravenously for 10 days and for at least 2
cycles. Only 2 (20%) obtained a CHR with a median OS of only 15 weeks. Main toxicity was
69
neutropenia in 19 patients (76%) and a median duration of 13 days . These results shows limited
efficacy of this regimen. Another study with a number of patients limited to 5, tested a different
hypomethilating drug, 5-azacitidine, with a 2nd generation TKI (dasatinib or nilotinib). All patients
achieved a CHR and 2 a CCyR. Tolerance of 5-AZA + TKI was acceptable, without grade 3 or 4
extra-haematological toxicity observed, but all patients experienced a grade 3-4 neutropenia or
thrombocytopenia 70.

9
 Homoharringtonine is an ester of the alkaloid cephalotaxine isolated from the Cephalotaxus
species, a Chinese tree, which inhibits the synthesis of proteins leading to apoptosis and induces
71, 72
responses alone or in combination in various phases of CML . Homoharringtonine is effective
in imatinib resistant CML and it is cheaper than 2nd generation TKI, especially relevant for low-
income Countries. In a Chinese study 12 patients with myeloid BP CML (already with several lines
of therapy and including imatinib, interferon-± and ARA-C) were treated with an association of
homoharringtonine, imatinib and G-CSF. Of the 11 patients evaluable for response, 7 patients
73
obtained CHR and 3 a CCyR, and 8 patients underwent HSCT . A subsequent synthetic form of
homoharringtonine was developed and omacetaxine mepesuccinate is currently approved by the
Food and Drug Administration as 3rd line therapy in CML 74
. In a Phase II, study 44 patients with
BP CML were treated with omacetaxine 1.25 mg/m2 BID administered on days 1 to 14, every 28
days, for up to six cycles. Only 3 patients had a CHR, without any MCyR. The most common AEs
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were grades 3-4 myelosuppression (thrombocytopenia 30%, anaemia 21%, neutropenia 21%) that
75, 76
was associated with grade 3-4 infection-related events in 32% cases . The above cited results
are summarized in Table 2.

5. Other future (investigational) drugs

Many other compounds are being currently tested in the setting of advanced CML, their future role
in management of BP CML could be beneficial. Thereafter, we well summarise some
investigational agents (table 3).

77
Danusertib is a dual inhibitor of pan-Aurora kinase and also BCR/ABL1, including T315I . A
phase I study was recently concluded and observed response in 4 patients (20%) with AP/BP
CML. The most frequent drug-related events were constipation, diarrhoea, mucositis, nausea,
78
fatigue, thrombocytopenia and febrile neutropenia . The small molecule MK-0457 is another
inhibitor with combined activity against the Aurora kinase family and ABL (including the imatinib-
resistant T315I), and anti-FLT3. In a phase I/II 8/18 (44%) patients with CML and a T315I mutation
had a hematologic response with MK-0457; gastrointestinal toxicities, including mucositis, were
79 80-82
relatively common . Based on results of early studies in AML , also barasertib (a selective
Aurora kinase B inhibitor) could possibly represent a drug to be evaluated in BP CML.

Axitinib is an anti-angiogenetic, VEGFR inhibitor, FDA-approved for the treatment of renal cell
83, 84
carcinoma, which has demonstrated preclinical efficacy in TKI-resistant CML . Axitinib has also
85
ability to bind and inhibit T315I mutated ABL1 . Clinical studies of axitinib efficacy in drug-
resistant BCR/ABL1 (T315I)-driven leukaemias could be stimulating, also by the consideration of
the possibility of approval in a fast-track mode.

10
 Some pre-clinical evidences suggest a possible synergic effect of arsenic trioxide (ATO) with TKI
86
(nilotinib) on BP-CML cells . This combination would be interesting given the experience already
available about the safety of ATO in the setting of acute promyelocytic leukemia.

A different therapeutic approach which may be promising is the use of non-ATP-binding site
inhibitors of BCR-ABL (GNF-2, ABL001), that are currently in phase I trials 87-90.

Finally, the efficacy of BCL2 inhibitors (eg. venetoclax (ABT-199), navitoclax and sabutoclax) in BP
CML has recently been proposed by some studies, which have shown that the inhibition of Bcl-
84, 91
2/Bcl-xL induce apoptosis of quiescent CML progenitor cells . Moreover, the combination of
TKIs and BCL2 inhibitors might have synergistic effects in TKI-resistant patients 92, 93.

6. Allogeneic stem cell transplantation

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HSCT is particularly effective and potentially curative in CP CML, because of the demonstrated
effect of Graft-versus-leukemia (GVL) in CML. In fact, donor lymphocyte infusions (DLIs) could
94-97
achieve stable second remissions in CML patients relapsing after HSCT and incidence of
relapse was more frequent in T cell–depleted recipients and in patients without graft-versus-host
98
disease . Three-year survival probability after transplantation of patients in chronic phase was
reported to be 91% 99.

For BP CML, prompt referral to a transplant center and search for HLA-compatible donor is critical
how is suggested by a retrospective Chinese study comparing TKI vs. TKI+HSCT, by patient
100
choice, resulting in a 5-year OS of 9.1% in TKI alone and 44.9% in TKI+HSCT . Those findings
rd
are also confirmed in the setting of patients treated with a 3 generation TKI ponatinib in the
56
previously mentioned study from Nicolini et al. .

HSCT represents the only possible curative treatment, but it cures less than 10% of patients
101
transplanted in frank blast crisis . Therefore, any attempt to adopt a therapeutic strategy as
bridge to reach at least a CHR should be undertaken. Unfortunately, even in patients transplanted
in recent years (2000 to 2003) in BP CML results are quite disappointing with a 2-year OS of 16%,
102
a transplant-related-mortality (TRM) of 50% and a cumulative risk of relapse of 38% . The
German CML Study IV that was conducted in imatinib-era reported better results. In this study, the
99
3-years OS after transplant was 59% in the 28 patients in accelerated or blastic phase CML .
From the latest CIBMTR analysis of HSCT for BP CML in the TKI-era the reported 3-year OS was
14% 103.

Strategies to reduce relapses after HSCT encompass regular MRD monitoring and DLI infusion
104
(usually escalating doses are infused in the attempt to reduce GVHD ) and by TKI prophylaxis.
105, 106
After HSCT, imatinib is safe generally with limited gastrointestinal toxicity . Interestingly,

11
 patients treated with imatinib after HSCT experienced less GVHD, probably because imatinib
105
inhibits intracellular signalling of fibrotic cytokines like TGF² and PDGF . Moreover, TKI + DLI
107
can be usefully associated after HSCT . In a study comparing the 3 therapeutic options (TKI,
DLI, TKI + DLI) after CML-relapse after HSCT the best results were seen with TKI alone, even if
the difference was not statistically significant 108.

To sum up, in the absence of specific data deriving from prospective trials in BP CML, the
opportunity of HSCT should be offered according to ELN recommendations 1.

7. Conclusions

The advent of TKIs has reduced the rate of progression to BP and allowed the possible treatment
of patients who progressed, but only marginally changed their outcome. Even if favourable
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responses can be achieved in a part of patients treated, including hematologic or cytogenetic

remissions, these responses are usually transitory. In most occasions, TKIs alone or in
combination with conventional chemotherapy, provide a possible bridge to transplant. Nowadays,
HSCT remains the only curative option for the category of advanced phases of CML. Further
biological and clinical studies are strongly warranted in this setting to improve results and long-term
outcome.

8. Expert opinion

Dissecting the pathogenetic role of BCR-ABL1 in CML patients has allowed the introduction of new
TKIs and drastically revolutionized the outcome of chronic phase setting. Moreover, the
standardization of molecular response enables to early identify primary resistant patients or early
relapse, which permits to prevent progression of disease. Mechanisms of resistance are defined
for more than 50% of patients who progressed and usually are imputable to kinase domain
mutations. Unfortunately, all these advances have had an impact on the long-term prognosis of
patients in chronic phase, except in blastic phase. In BP, TKIs induced improved responses but
usually transient and not durable, therefore allogeneic bone marrow transplant remains the only
curative option for a minority of eligible patients and with a compatible donor. Not all TKIs available
for BP are equivalent and for example, for central nervous system (CNS) localization, dasatinib, as
compared to other TKIs available, penetrate the brain blood barrier, reaching increased
concentrations. Currently, only sponsored or cooperative clinical trials were reported and a lack of
data exists for patients treated in daily clinical practice in large series of real-life patients. In
particular, only for lymphoid Ph+ BP-CML results of intensive chemotherapy in association with
second or third generation TKIs have been reported: there is an absolute lack of data for the best
chemotherapeutic strategies to adopt for myeloid BP patients. What is the best regimen for this
12
 setting and when to start with TKI (first day of chemotherapy or at the end of intensive treatment),
based on the results of mutational status, is indeed not clear. Moreover, there is a need to clarify
drivers for resistance through BCR-ABL1 dependent and independent pathways that can lead to
the persistence of residual stem cell compartment. Newer generation TKIs effective in the setting
of patients in advanced phases and that escape from usual mechanisms of resistance are needed:
is actually being investigated an inhibitor, the ABL001, a potent allosteric drug able to bind a
different region, the myristoylated side, and forcing a conformational change that disables active
site. A phase 1 trial is ongoing to determine the MTD and also BP patients are allowed to be
included. This drug could be an example of alternative approaches focused on the prevention of
relapse and the eradication of blastic stem cell. Other drugs, such as PRI-724 (a small molecule
that inhibits Beta-catenin-driven genes) or anti-PD1 (PD-1 antibody with the aim to interrupt
immunotolerance of cancer cells) are already tested and could represent possible association
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strategies. In the future, those drugs could be tested in association with other TKIs or with standard
chemotherapy. Scarce evidences have been reported since now about best treatment strategies
for BP patients: tailored chemotherapy associated to TKIs is recommended and doses should be
decided according to patient’s conditions. Final endpoint in this setting, considering the pre-
existence of comorbidities, age at the time of progression and donor availability, is to perform a
bone marrow transplant: unfortunately, significant data published in large series of patients who
underwent allogeneic transplant in BP are not been reported and the exact conditioning regimen
(myeloablative or not) is still an open question. Moreover, also if the same TKI used before
transplant has to be restart, as pre-emptive therapy, remain a matter of discussion. Actually,
physicians are strongly encouraged and suggested to follow international guidelines to manage
CML patients who progressed or who were diagnosed as de novo BP.

13
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 Table 1. Studies on TKIs in BP CML.

Drug Year N. pts CHR CCyR Median OS Median

Author
duration
OS at Last
Reference of
available FU
response

Druker 25 Imatinib 1999- 38 My 55% 12% NA 58 days

2000
20 Ly NA

Sawyers Imatinib 1999- 229 My 34% 9% 6.9 mon. 4 months

2008
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Silver 26, 27 6% at 2009

Imatinib 2002 65 My 23% 16% 6.5 mon 3 months

Kantarjian 28
10 Ly 28% at 1 yr.

Palandri 29 Imatinib 2001- 72 My 50% 10% 7 months. 11

2009 months
20 Ly 11% at 36
mon.

Talpaz 37 Dasatinib 2006 23 My 35% My 35% My NA ~6

months
10 Ly 70% LY 80% LY

Cortes 38, 39 Dasatinib 2007 109 My 27% My 26% My 11.8mon.My 6.7 My

48 Ly 29% LY 46% LY 5.3 mon. Ly 3 Ly

Saglio 40 Dasatinib 2010 149 My 28% My 14% My 8 mon.My 3.8 My

61 Ly 42% LY 38% LY 11 mon. Ly 4.7 My

24% at 2 yrs

Kantarjian 42 Nilotinib 2006 24 My 2 2 NA NA

9 Ly

Giles 43 Nilotinib 2008 105 My 24% My 30% My 10 mon.My 24 My

31 Ly 41% LY 32% LY 8 mon. Ly 13 My

42% at 2 yrs

20
 Nicolini 44 Nilotinib 2006- 130 My 7% My 8.3% My 63% at 18 NA
months
2007 50 Ly 14% LY 26% LY

Gambacorti- Bosutinib 2014 36 My 27% My 3% My 10.9 months 8 months

Passerini 46 28 Ly 4% LY 4% LY 23% at 4 yrs

Cortes 54 Ponatinib 2008- 8 36% 32% NA NA

2010

Cortes 55 Ponatinib 2010- 62 31% 23% 7 months 4 months

2011 29% at 1 yrs

(CHR: Complete haematological response; CCyR complete cytogenetic response; OS: overall
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survival; DOR: median duration of response; NA: not available; MY: myeloid; Ly: lymphoid)

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 Table 2. Outcomes in BP-CML patients with TKI in association with chemotherapic/novel agents

Author Drug Year N. pts CHR CCyR Median OS Median

DOR
Reference OS at Last
available FU

Rea 61 Imatinib, 2001- 31 Ly BP 84% 19 12 months 9.5 mo

vincristine, (18 ALL
2004 2 MMR 20% at 2 yrs
Ph+
Dexamethasone

Strati 62 Hy-CVAD+ 2001- 42 Ly BP 90% 57% 17 months 14 mo

imatinib or 2011 25% MMR

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dasatinib

Imatinib, araC, 2002- 19 My BP 26% 47% 48% at 1 yr ~3 mo

Quintas-
idarubicin
Cardama 66 2004

Deau 67 Imatinib, araC, 2001- 37 My BP 77% 55% 16 months 27 mo

daunorubicin
2005

Milojkovic 68 FLAG/IDA + 2012 4 100% 75% NA NA

dasatinib
1 MMR

Oki 69 Decitabine + 2007 10 2 2 3 months NA

imatinib

Ghez 70 Azacitidine + 2013 5 5 2 4 Alive at 2 yrs NA

dasatinib/nilotinib

Fang 73 Homoharringtonine 2010 12 7 3 75% at 1 yr NA

+ imatinib

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 Table 3. List of investigational drugs in BP CML.
AML acute myeloid leukemia; VEGF vascular endothelial growth factor. * in AML

Reference Drug Target Clinical trial number

(NCT)
[78] Danusertib Aurora kinase + BCR/ABL1(also NCT00335868
T315I)
[79] MK-0457 Aurora kinase + BCR/ABL1(also NCT00111683
T315I) NCT00500006
Barasertib Aurora kinase-B NCT00530699
[80-82] *
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(AZD1152-HQPA)
[83-85] Axitinib VEGF receptor + NCT00071006
BCR/ABL1(also T315I) NCT02638428
[90] ABL001 BCR/ABL1 (allosteric inhibition) NCT02081378
[92, 93] Venetoclax (ABT-199), BCL2 (apoptosis) NCT01994837 *
Navitoclax

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