How I treat newly diagnosed chronic myeloid leukemia in 2015

How I treat newly diagnosed Chronic Myeloid Leukemia

Carlo Gambacorti-Passerini MD1*, Rocco Piazza MD, PhD1

1 Department of Health Sciences, University of Milano-Bicocca, Section of Hematology, San

Gerardo Hospital, Monza, Italy.

* corresponding author:

Prof. Carlo Gambacorti-Passerini

Department of Health Sciences, University of Milano-Bicocca

Via Cadore, 48

20900 Monza, Italy

E-mail: [email protected]

Phone number: +39 039 2339553

Abstract – Word Count: 141

Text – Word Count: 3982

Figure Count: 2

Table Count: 1

Running Title: First line treatment in CP-CML

Keywords: CML, clinical trials, quality of life, long term survival, late effects

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/ajh.23887

2

ABSTRACT

The initial treatment for Chronic Myeloid Leukemia in Chronic Phase (CP-CML) represents a

complex process, which includes a prompt and precise diagnosis, the choice among 3

available Tyrosine Kinase Inhibitors (TKIs) and additional therapies, and the initial

management of care for these patients, which will protract over a very long period of time.

This manuscript summarizes different data on activity, side effects and supportive measures

available for each TKI, the need for particular care in the logistical organization of CML

management, the scenario which will be opened by the future availability of generic imatinib.

The opinion of the authors is that imatinib remains the first line treatment for CP-CML; this

strategy, accompanied by intensive monitoring and possible dose modification/drug switch

after the initial 3-12 months of treatment presently assures a normal life expectancy to the

population of newly diagnosed CP-CML patients.

Introduction

Chronic Myeloid Leukemia (CML) treatment and prognosis were dramatically improved by the

development and clinical use of imatinib mesylate [1-3], the first ATP-competitive inhibitor

active on ABL [4-6]. After 15 years of clinical use of imatinib results are so satisfactory that in

CML patients who obtained and maintained Complete Cytogenetic Response (CCyR), or

even in newly diagnosed CML patients, survival is indistinguishable from that of the general

population [7, 8], making CML the first cancer in which a medical treatment can return

patients to a normal life expectancy [9] (Figure 1). The extent of this progress has to be

evaluated by considering the expected survival (2-3 years) for CML patients in the so called

“pre-imatinib era” [10, 11] (Figure 2). These results have been rendered possible by the

combination of two characteristics of imatinib: its high activity against CML, with a minority of

deaths during treatment with imatinib being due to CML [3], and its remarkable safety profile,

with very rare treatment-related serious toxicities or deaths. The excellent long term prognosis

of CML must therefore be taken into serious consideration when proposing alternative or

experimental treatments: the bar for ethically acceptable risks must be raised substantially.

The recent availability of 2nd and 3rd generation TKIs for both first and second-line treatment

of CML and the need for specialized diagnostic tools renders the clinical management of CML

more complicate. Four additional TKIs are available to treat CML: dasatinib, nilotinib,

bosutinib and ponatinib [12-15]. Radotinib, a nilotinib analogue, is registered in South Korea

[16]. Dasatinib and nilotinib are also approved for first line treatment of CML [17, 18].

Therefore the initial choice of therapy for a newly diagnosed CML patient represents today a

complex process, in which different, sometime conflicting factors are compounded and must

be considered in order to offer the best treatment option to our patients. The following case

Page 2 of 19

John Wiley & Sons

American Journal of Hematology

3

describes several issues to be considered when deciding treatment for newly diagnosed CML

patients.

Case description

PC is a 59 years old gentleman. He is also the VP of a large Italian energy company. He flies

overseas at least once per month and conducts a very active life. Given his position, his

company asks him to undergo an annual health check. Six month earlier he had the latest

one. Although WBC were already alarmingly high (17500 / cmm) the company physician

seemed more interested by his cholesterol and triglycerides levels and advised him to limit

cheese and animal fat intake. Six months later the patient presented to a local ER

complaining of the acute onset of left flank pain and of increasing asthenia that did not allow

him to keep up with his hectic life style. His WBC were 87,000, with 2% peripheral blasts and

his spleen lower margin could be palpated 19 cm below the left costal margin, with a Sokal

score of 1.6, placing him in the so called “high risk group”. Abdominal US scan revealed a

small splenic infarct. Cytogenetic analysis showed 20/20 Ph+ metaphases and bone marrow

analysis confirmed the diagnosis of chronic phase (CP, blasts 4%) CML. I discussed

extensively (for about an hour) with the patient and his wife the practical meaning of the

diagnosis, the safety/toxicity profiles of all available alternatives, including Bone Marrow

Transplantation (BMT) and experimental protocols available at my institution. BMT was

excluded by the patient given the >30% Treatment Related Mortality connected with the

procedure in his case (EBMT score 3-4). In the end the patient opted to start imatinib, which

was prescribed at the dose of 400 mg/day. The treatment was tolerated well, with grade I-II

periorbital edema and muscle cramps as the main complaints. Splenomegaly resolved after 3

weeks and CHR was achieved by the 4th one; although the BCR-ABL1 transcript level

measured by RT-PCR at 3 months was 13% and cytogenetics showed a PCyR, he obtained

CCyR at month 6 and MMR at month 14. His latest molecular response (at month 36) is MMR

4.0 but his PCR seldom tests negative. During long-term use of imatinib we noted that his

skin became less resistant to traumas, one of the most frequent long-term effects of imatinib

[7]. He resumed his usual life style after the initial 6 months of therapy and became one of the

founders of the Italian Association of CML patients.

This case epitomizes several issues and decision points that characterize the early

management of CML.

Initial diagnosis

When PC was initially diagnosed with CML, his disease was still in CP but his Sokal score

was already “high”. This condition meant that his chances of obtaining a CCyR by the end of

the first year of treatment, one of the most important predictors for the long term control of the

Page 3 of 19

John Wiley & Sons


4

disease, were reduced by 27% or 18% when compared with a patient with a low or

intermediate Sokal score, with an increase in the risk of progression of CML over the first 5

years [3, 19]. It is likely that, should the initial leukocytosis not have been overlooked six

month earlier, he would have been diagnosed in the intermediate or even in the low Sokal

score groups, with a clear improvement in his prognosis. This fact epitomizes the importance

of not overlooking any leukocytosis, discounting it as “secondary”, without rechecking WBC

values a couple of weeks later. The amount of damage that a delay or a mistake in the

diagnosis or in the management of CML can cause to a CML patient can be compared to that

caused by a similar behavior in the diagnosis of a treatable condition such as acute

appendicitis. The time scales in the two conditions are obviously different (hours/days versus

months/years) but the extent of potential damage (normal life expectancy versus death) is

similar.

Choice of treatment

There are 3 TKIs registered for first line treatment of CP-CML. Imatinib became clinically

available in 1999 and was licensed for use in IFN-resistant/intolerant CML patients in 2001

[20]. First-line indication came in 2003. Since then >100,000 patients received the drug with

some patients now on treatment since more than 15 years. Both registrative [1-3, 19, 21-23],

and independent [7, 8, 24-29] studies have confirmed its activity and safety, including

independent long-term analyses. Imatinib is the only drug for which independent studies

demonstrated a normal or near normal life expectancy in treated patients [7, 8, 26]. Since

imatinib represents the drug available for the longest period of time, it is also the one that is

most familiar to hematologists and oncologists worldwide. In fact with the increased clinical

experience available on imatinib and when its use is applied within an optimal logistical

management context (i.e. in a dedicated CML clinic [see below]), a normal life expectancy is

possible today for CML patients at diagnosis, with CCyR rates at 12 months >80%, MMR

rates >50% at 24 months and a risk of progression to AP/BC in the initial 2 years of 0-3% [8,

30]. It is important to note that part of these excellent results derive from the availability of 2nd

and 3rd generation TKIs, to rescue the few resistant/intolerant patients. Adverse events linked

to imatinib are usually non dangerous, with the very rare occurrence of acute liver failure and

Steven-Johnson syndrome (http://www.glivec.com/files/Glivec-100mg-coated.pdf). Side

effects however are perceived by patients as bothering and can interfere with their Quality of

Life (QoL): edema, fatigue, cramps, skin fragility, diarrhea are seldom serious but they

develop over time in the majority of patients [7, 31] and require a solid relationship between

physician or other health professionals and the patient and his/her family, in order to cope

with them and to reduce non-compliance (see also the next section). At our center we found

that Potassium and/or Calcium supplements are useful in the control of cramps, while

diuretics can control excessive peripheral edemas. In addition patients with stable responses

are told about the possibility of taking, after discussion with the physician, 1 or two planned

drug holidays (2-3 weeks) per year, in order to lessen the psychological burden of a life-long

Page 4 of 19

John Wiley & Sons


5

treatment. As it happens for most therapies, old patients with several comorbidities tend to

experience higher rates of adverse events [32] but similar therapeutic activity [27]. An earlier

report suggested that imatinib could exert a cardiotoxic activity [33]; however later studies

failed to confirm this statement [34, 35]. Although there are no controlled studies of imatinib

versus placebo available, the fact that no excess deaths are present in CML patients treated

with imatinib compared to the general population [7, 8] supports the benign safety profile of

this drug. While imatinib brings CML under indefinite control in most patients, quiescent stem

cells [36] persist in the majority of them, biologically refractory to BCR-ABL inhibition [37], and

cause persistent RT-PCR positivity. Even durable (>2 years) PCR negativity, which develops

in 20-40% of imatinib treated patients over time [3, 7], is followed by molecular relapse in

approximately half of the cases upon imatinib discontinuation [38-42], meaning that no more

than 10-20% of imatinib treated patients can permanently discontinue the drug. In conclusion,

imatinib dramatically changed the natural history of CML; the drug shows a safe toxicity

profile, although the majority of patients complain about some subjective adverse events; it

confers a normal or near normal life expectancy to CML patients (thanks also to the

availability of 2nd and 3rd generation TKIs used as second/third line treatments); it needs to be

continued indefinitely in the majority of patients.

Second generation TKIs

In 2010 both dasatinib and nilotinib were licensed for first line treatment of CML [17, 18].

Both drugs were initially developed to treat patients who became resistant to imatinib. They

are structurally different: dasatinib is a dual ABL/SRC inhibitor and possesses a broad

spectrum of targets [12], while nilotinib is structurally related to imatinib, shows an apparently

restricted panel of targets, with a preferential activity on ABL rather than PDGFR, at

difference with imatinib [13]. Their first-line registration was based on two controlled, company

sponsored studies, the DASISION and ENEST trials which enrolled approximately 250

patients in each arm. The published results of the two studies [17, 18] are rather similar: the

extent of tumor load, as evaluated by Q-PCR (quantitative PCR) for BCR-ABL1, decreased

more rapidly in patients treated with the 2nd generation TKIs during the first year; patients on

imatinib took approximately double time to reach the same level of molecular remission,

although they tended to narrow this gap subsequently [43-45]

(http://www.medicines.org.uk/emc/medicine/26080).

At 12 months the CCyR response rates are 11-15% higher in patients receiving 2nd

generation TKIs. More importantly, both dasatinib and nilotinib appear to decrease the

incidence of progression to AP/BC during the 1st-2nd year of treatment between 2 and 3.5%

over imatinib [43, 45] .

Page 5 of 19

John Wiley & Sons


6

In spite of these apparently superior data and of an aggressive marketing toward 2nd

generation TKIs, imatinib continues to represent the most commonly used TKI to treat CML

front line. How is this possible?

A number of possible causes have to be factored in.

- Nor dasatinib neither nilotinib ever showed substantial amelioration in either OS of PFS

rates over imatinib [43, 45] . In fact, when imatinib fails, >50% of patients can obtain

new durable responses using 2nd or 3rd generation TKIs [12-15]. In addition a recent

replica of ENESTnd (ENESTChina) did not show any significant difference between

imatinib and nilotinib in OS, PFS, progression to AP/BC, CCyR rates; the only

significant difference observed was in the rate of MMR at 12 months [46]. It has to be

remembered that it has been always quite difficult to discern an independent

prognostic value for molecular responses outside of cytogenetic ones [47]. If obtaining

“faster and deeper” responses with 2nd generation TKIs does not convert into a change

in prognosis, this phenomenon should not dictate a change in therapy by itself.

- Independent, long-term confirmation of these data is generally lacking, and in the only

case in which an independent controlled study was carried out [48], the results

confirmed the higher cytogenetic and molecular response rates with dasatinib but failed

to confirm the most clinically relevant finding: the protection from disease progression.

In addition, problems in ENESTnd in tracking the real reason for treatment

discontinuation, especially for patients who died after the 30 day period following drug

discontinuation [49], render the conclusions of a single study less definitive - Second

generation TKIs do not come free of adverse events.

Dasatinib targets the SRC family of TK, which are involved in signal transduction in lymphoid

cells, and results in NK cells expansion; this causes a dysregulation in the immune function

by causing a “proinflammatory” phenotype in which specific responses are suppressed in

favour of non-specific ones, causing lymphocytosis and several inflammatory side effects

such as serositis and panniculitis [13, 50]. Pleural and pericardial effusions represent a

particular problem, as they occur with frequencies ranging from 10 to >30%, can develop

years after treatment initiation and can recur even at lower dosages, causing treatment

interruptions and discontinuation. Consistent with a reduction in specific immune responses,

some additional reports emphasized an apparent increased susceptibility to infections in

patients treated with dasatinib, due also to an inhibitory role of this drug on neutrophil function

[51]. Finally, dasatinib was linked to some cases of primary pulmonary hypertension, a

potentially fatal lung condition [52]. Nilotinib was developed to increase ABL selectivity, and

indeed its activity is more pronounced on this TK than on the usual off-targets of ABL TKIs:

KIT and PDGFR. In spite of this fact, nilotinib is associated to a “Metabolic Syndrome” in

which the drug causes increased level of glucose, cholesterol and triglycerides, and

decreases the viability/motility of endothelial cells [53]; this in turn accelerates the progression

of atherosclerotic lesions and can cause clinical diabetes and arterial thrombosis such as

Page 6 of 19

John Wiley & Sons


7

myocardial infarction, stroke and peripheral arterial obstructive disease (PAOD)[54, 55].

These effects are even more surprising since the metabolic effects of the parent molecule,

imatinib, are opposite [56]. The molecular mechanisms underlying these adverse events are

still under investigation, and unfortunately also its real burden. In fact no reliable, published

exposure-adjusted rate for cardiovascular adverse events linked to nilotinib is available;

extrapolation from the above referenced manuscripts and from a recent publication [57] would

indicate a number between 3 and 5 events/100 persons years, while a recent presentation of

a company-sponsored analysis suggested that nilotinib would not increase such a risk and

imatinib would play a protective role instead [58]. This interpretation however is contradicted

by recent data derived from a controlled trial of bosutinib versus imatinib, in which the two

drugs showed similar values for both incidence and exposure-adjusted-rates of

cardiovascular adverse events [59, 60]. The onset of clinical diabetes can be observed in up

to 18% of nilotinib treated patients. Whatever the real numbers of nilotinib-associated

metabolic and vascular events are, they must be placed and evaluated in the general context

and prognosis of newly diagnosed CP-CML patients.

The cardiovascular toxicity of nilotinib also teaches us an important lesson on the need for

independent and long term studies. While the effusion problem linked to dasatinib was

already evident in the phase II publication [12], no hint to the cardiovascular toxicity linked to

nilotinib was present either in the phase II [13] or in the initial phase III reports [18]. The

observed adverse events of 2nd generation TKIs also raise another important point. Since the

prognosis for first line treatment of CML is excellent, with normal or near normal life

expectancy, the amount of risks that it is ethical to propose to a patient in this condition needs

to be adjusted to his/her overall prognosis, and therefore must be very low, especially when

irreversible damages can be caused. In such a case, the risk of a serious and irreversible

event within the 5%-10% range should be considered ethically questionable, and would easily

erase the supposed protection from CML progression.

A last consideration pertains to the deeper molecular responses obtained with 2nd generation

TKIs. While the proportion of patients reaching MMR (or MR 3) tends to become closer over

time in patients treated with imatinib or 2nd generation TKIs [43-45], 2nd generation TKIs

appear superior in reaching deeper responses (MR 4 or MR 4.5) [43, 45, 61]. Whether these

results will translate into a substantially higher proportion of patients who will be able to

discontinue their TKIs, it represents a fascinating scientific hypothesis, which however has not

been confirmed up to now. Basic biological data are not in favor of such an hypothesis [36,

37]. More important, these studies must again balance potential therapeutic and adverse

effects in a population with normal life expectancy, as discussed earlier. For example, the

ENEST-CMR study [57] randomized 207 CML patients in CCyR since >2 years (and therefore

with a normal life expectancy [7]) between continuing imatinib and shifting to nilotinib.

Although the primary endpoint of the study (confirmed PCR negativity at 12 months) was not

met, the trial showed that a significant number of patients randomized to nilotinib achieved

deep molecular responses. These results however were obtained at the cost of 1 death and

Page 7 of 19

John Wiley & Sons


8

of 7 cardiovascular events in the nilotinib arm (out of a total number of 101 patients treated

with nilotinib for 2 years), compared to 1 cardiovascular event in the imatinib arm.

Type of management

Once CML was diagnosed and patient PC started treatment, he was seen every week in the

first month of therapy at a dedicated CML clinic, with the main aim of checking his WBC,

discussing side effects and building a solid relationship. The patients was seen once per

month in the first year and every 3-4 months thereafter; cytogenetic analysis was performed

at months 3, 6, (9), 12, 18, 24, 36 and 60, while Q-PCR was performed every 3-4 months or if

clinically indicated. We routinely do not perform Q-PCR during the first 3 months of treatment

but are considering this possibility [62]. While cytogenetic response is a sturdy technique, has

a high biological value (it tells if the patient’s hemopoiesis is prevalently leukemic or normal)

and guards against the possible presence of genetic lesions in Ph negative metaphases [63],

molecular analysis through Q-PCR remains instead of fundamental importance for the long

term monitoring of the disease, given its non-invasive and highly sensitive nature.

Even when appointments became less frequent, Mr. PC was always seen by the same team

of two doctors. When arriving at the clinic he was first interviewed by nurses, and then was

seen by the doctor. This “double” recollection of data has been very useful to identify

problems with compliance and quality of life issues that although not severe could jeopardize

drug efficacy through irregular dosing. Patients tend to tell different aspects of their life to

nurses and to doctors; in addition, the stable relationship built over time with patients is vital to

guarantee optimal results. Connections established among the patients themselves are also

important and are facilitated by a dedicated CML clinic where they initially meet. It is also

important for patients to exchange experiences among peers, also through the establishment

of CML patients associations, run and managed by patients (e.g.

http://www.aipleucemiamieloidecronica.it, http://www.vivreaveclalmc.org, http://www.lmc-

france.fr, http://www.cmlsociety.org, http://www.nationalcmlsociety.org,

www.cmlsupport.org.uk).

Such a care requires constant attention on the part of physicians who need to devote

sufficient time to the seemingly unproblematic CML patients. An essential aspect to consider

in this respect is the availability of a dedicated CML unit. The presence of other hematological

patients in the same clinic at the same time, often with more urgent medical needs, will

inevitably curtail the time available for CML patients and thus will damage the provider-patient

relationship. The ADAGIO study found indeed that the two main variables associated to

treatment adherence (and to long-term responses) in a group of 202 CML patients were the

Page 8 of 19

John Wiley & Sons


9

number of CML patients seen at that center (and thus the probable existence of a dedicated

CML clinic) and the duration of the first visit [64]. The relationship between response and

logistical organization of CML care is dramatically confirmed by the very low rate of CCyR at 1

year (27/151, or 18%) obtained with imatinib first line treatment of CP-CML in Ife-Ife, Nigeria

(M Durosinmi, personal communication), where important logistical problems (lack of RT-

PCR, procurement of drug, power outages, general instability, cultural problems in the

acceptance of chronic medical treatment) hampered the efforts of physicians in the past, in

addition to the lack of a dedicated CML clinic. Thus the CCyR rates at 12 months show huge

variations (table I), from values close to 90% in recent single center experiences [23, 30], to

65-72% in older multicenter registration studies [16, 17], to 41% in older population based

registries [29], to 18%, using the same drug but in different logistical/management contexts.

These numbers should alert physicians on the importance of time spent with CML patients

and on the organization of care, in comparison to the type of drugs used. We must remember

that even an entire hour devoted to a CML patient is economically equivalent to the cost of

few days of treatment and can have a substantial and long term impact on the outcome [64];

the ability to spend enough time with patients is generally viewed by physicians as one of the

largest limitations to a positive professional practice [65].

Therefore the management of care for CML patients involves a number of different subjects

(physician, nurses, other health professionals, families and friends, hospitals/insurance

managers, pharmaceutical companies) and issues (availability of 2nd generation TKIs,

intensive monitoring, dedicated CML clinic). It is important that the final goal of this complex

and coordinated approach remains the health of the patients.

Conclusions

In our opinion imatinib represents the best choice for first line treatment of CP-CML, based on

its therapeutic activity, safety profile and availability of long term data in a high number of

patients. However we do not “start treatment”, rather we inform and discuss with patients the

different treatment options, their respective pros and cons, and then let them to decide. Our

experience during these years has been that first line 2nd generation TKIs were chosen by

patients in only 3 out of 105 cases, outside of participation in controlled clinical trials. The

availability of 4 additional TKIs for second line use represents a fundamental asset in the

physician armamentarium.

Equally important is that CML patients need to be followed with close attention by a physician

expert in CML and that care has to be managed inside a dedicated CML clinic where

treatment and monitoring are optimally organized.

The decision to change treatment in nonresponsive patients has to be based at present

mainly on personal experience and available information (i.e. rate of decrease of Ph+ cells,

Page 9 of 19

John Wiley & Sons


10

mutational screening results, evidence of BCR-ABL1 gene amplification, polymorphism in

genes affecting drug entry or metabolism...), as no data from controlled studies exist. While

there is consensus that certain milestones (CCyR by 12 months, <10% transcript at 3-6

months) affect outcomes and therefore identify a population of patients with more aggressive

disease, there is no evidence from controlled studies that changing treatment at those time

points will improve their prognosis. In such a situation guidelines such as ELN [66] or NCCN

(http://www.nccn.org/patients/guidelines/cml/) can be useful but are, unfortunately, of limited

help.

A final consideration pertains to the cost of TKIs. Price for second generation TKIs ranges

between 30% and 100% higher than imatinib [67]. With the close advent of generic imatinib,

the differential cost is going to increase logarithmically, and it could become difficult to justify

their high cost when compared to the potential advantage in first line use, especially given the

resilience of the 50,000$/quality-adjusted life years (QALY) threshold to evaluate

cost/effectiveness of a given health care intervention [68].

Exclusion. Patients who are diagnosed with CML in advanced phase (Accelerated phase or

Blast Crisis) are excluded from the present manuscript. Their number is so low and available

studies are so limited that no opinion can be expressed; studies in this population are urgently

needed.

Acknowledgments

We thank Dr. Muheez A. Durosinmi, (Department of Haematology & Immunology, Obafemi

Awolowo University, Ile-Ife, Nigeria) for communicating clinical data of CML patients in Ile-Ife.

Moreover we thank Dr. Nicoletta Cordani for her vital support in editing and work revision.

Funded by Associazione Italiana per la Ricerca sul Cancro (AIRC 2013 IG-14249 to CGP).

This manuscript was initially commissioned by Blood. However after evaluating it the journal

declined publication.

Authorship contribution

CGP designed and wrote the manuscript. RP critically reviewed the manuscript.

Conflict of Interest

CGP: Pfizer, research grant and scientific board fee; BMS, speaker fee. RP: none

Page 10 of 19

John Wiley & Sons


11

References 1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037. 2. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-652. 3. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417. 4. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561-566. 5. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 1997;23:380-394. 6. Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997;90:3691-3698. 7. Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011;103:553-561. 8. Vigano I, Di Giacomo N, Bozzani S, et al. First-line treatment of 102 chronic myeloid leukemia patients with imatinib: A long-term single institution analysis. Am J Hematol 2014;89:E184-187. 9. Smith BD. Imatinib for Chronic Myeloid Leukemia: the impact of its effectveness and long-term side effects. Journal of National Cancer Institute 2011;103:527-529. 10. Rebora P, Czene K, Antolini L, et al. Are chronic myeloid leukemia patients more at risk for second malignancies? A population-based study. American journal of epidemiology 2010;172:1028-1033. 11. Bjorkholm M, Ohm L, Eloranta S, et al. Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol 2011;29:2514-2520. 12. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. The New England journal of medicine 2006;354:2531-2541. 13. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. The New England journal of medicine 2006;354:2542-2551. 14. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011;118:4567-4576. 15. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. The New England journal of medicine 2013;369:1783-1796. 16. Kim SH, Menon H, Jootar S, et al. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica 2014;99:1191-1196. 17. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. The New England journal of medicine 2010;362:2260-2270.

Page 11 of 19

John Wiley & Sons


12

18. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. The New England journal of medicine 2010;362:2251-2259. 19. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004. 20. Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002;8:935-942. 21. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002;99:1928-1937. 22. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:3530-3539. 23. Hochhaus A, Druker B, Sawyers C, et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 2008;111:1039-1043. Epub 2007 Oct 1011. 24. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:3358-3363. 25. Zackova D, Klamova H, Dusek L, et al. Imatinib as the first-line treatment of patients with chronic myeloid leukemia diagnosed in the chronic phase: can we compare real life data to the results from clinical trials? Am J Hematol 2011;86:318-321. 26. Hehlmann R, Muller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol 2014;32:415-423. 27. Gugliotta G, Castagnetti F, Palandri F, et al. Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood 2011;117:5591-5599. 28. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. The New England journal of medicine 2010;363:2511-2521. 29. Lucas CM, Wang L, Austin GM, et al. A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials. Leukemia 2008;22:1963-1966. 30. Cerrano M, Crisa E, Pregno P, et al. Excellent therapeutic results achieved in chronic myeloid leukemia patients with front-line imatinib and early treatment modifications in suboptimal responders: a retrospective study on 91 unselected patients. Am J Hematol 2013;88:838-842. 31. Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood 2011;118:4554-4560. 32. Breccia M, Luciano L, Latagliata R, et al. Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival. Leuk Res 2014. 33. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature medicine 2006;12:908-916.

Page 12 of 19

John Wiley & Sons


13

34. Gambacorti-Passerini C, Tornaghi L, Franceschino A, et al. In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate'. Nature medicine 2007;13:13-14; author reply 15-16. 35. Tiribelli M, Medeot M. Cardiotoxicity of imatinib: At the heart of the problem. Leuk Res 2011;35:36-37. 36. Jorgensen HG, Allan EK, Jordanides NE, et al. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007;109:4016-4019. 37. Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011;121:396-409. 38. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029-1035. 39. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515-522. 40. Benjamini O, Kantarjian H, Rios MB, et al. Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. Leuk Lymphoma 2013. 41. Breccia M, Alimena G. Discontinuation of tyrosine kinase inhibitors and new approaches to target leukemic stem cells: treatment-free remission as a new goal in chronic myeloid leukemia. Cancer Lett 2014;347:22-28. 42. Mori S, Vagge E, le Coutre P, et al. Age and Digital-PCR analysis predict relapses of CML patients following programmed imatinib interruption in Q-RT-PCR negatice chronic myeloid leukemia patients. Abstract 283p, EHA Milano 2014. 43. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494-500. 44. Hjorth-Hansen H, Stenke L, Soderlund S, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006). Eur J Haematol 2014. 45. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012;26:2197-2203. 46. Huang X, Wang J, Baccarani M, et al. Frontline Nilotinib Results In Superior Rates Of Molecular Response Versus Imatinib In Chinese Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): ENESTchina 12-Month Primary Analysis Abstract 1497, ASH 2013. 47. Marin D. Patient with chronic myeloid leukemia in complete cytogenetic response: what does it mean, and what does one do next? J Clin Oncol 2014;32:379-384. 48. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012;120:3898-3905. 49. Simonsson B, Porkka K, Richter J. Second-generation BCR-ABL kinase inhibitors in CML. The New England journal of medicine 2010;363:1673; author reply 1673-1675. 50. Assouline S, Laneuville P, Gambacorti-Passerini C. Panniculitis during dasatinib therapy for imatinib-resistant chronic myelogenous leukemia. The New England journal of medicine 2006;354:2623-2624.

Page 13 of 19

John Wiley & Sons


14

51. Futosi K, Nemeth T, Pick R, et al. Dasatinib inhibits proinflammatory functions of mature human neutrophils. Blood 2012;119:4981-4991. 52. Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:2128-2137. 53. Hadzijusufovic E, Albrecht-Schgoer K, Huber K, et al. Nilotinib Exerts Direct Pro-Atherogenic and Anti-Angiogenic Effects On Vascular Endothelial Cells: A Potential Explanation For Drug-Induced Vasculopathy In CML. Abstract 257 55th ASH Annual Meeting and Exposition New Orleans, 2013. 54. Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011;86:533-539. 55. Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst 2011;103:1347-1348. 56. Franceschino A, Tornaghi L, Benemacher V, et al. Alterations in creatine kinase, phosphate and lipid values in patients with chronic myeloid leukemia during treatment with imatinib. Haematologica 2008;93:317-318. 57. Hughes TP, Lipton JH, Spector N, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood 2014;124:729-736. 58. Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 2013;27:1310-1315. 59. Gambacorti-Passerini C, Kantarjian H, Khoury HJ, et al. Long-Term Assessment of Cardiac Toxicity in Patients with Ph+ Leukemias Treated with Bosutinib. Abstract 903: Haematologica 99(S1); 2014. 60. Cortes JE, Kantarjian HM, Khoury HJ, et al. Long-term evaluation of vascular toxicity in patients with Ph+ leukemias treated with bosutinib. Abstract 7060; J Clin Oncol 32:5s. 2014 ASCO Meeting. 61. Breccia M, Alimena G. Second-generation tyrosine kinase inhibitors as first-line treatment strategy in newly diagnosed chronic phase chronic myeloid leukemia patients. Curr Cancer Drug Targets 2012;12:391-401. 62. Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014;124:511-518. 63. Medina J, Kantarjian H, Talpaz M, et al. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003;98:1905-1911. 64. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009;113:5401-5411. 65. Jauhar S. Our ailing medical system. Wall Street Journal 2014:C1-C2. 66. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872-884. 67. Leukemia EiCM. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013;121:4439-4442.

Page 14 of 19

John Wiley & Sons


15

68. Neumann PJ CJ, Weinstein MC. Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold. N Engl J Med 2014;371:796-797.

Page 15 of 19

John Wiley & Sons


16

Tables

Table I. Comparison of CCyR rates in different types of studies on CML patients

receiving first line imatinib treatment.

Figure Legends

Figure 1. OS in 102 consecutive CML patients who received first-line imatinib

treatment. Numbers on the X axis represent patients at risk. (+): censored patients.

Source: from Viganò et al., 2014.

Figure 2. Estimated cumulative relative survival of chronic myeloid leukemia (CML)

patients by period of diagnosis (1970–1984 vs. 1985–1995), Sweden, 1970–1995. Fifteen-

year survival figures were 2.4% (95% confidence interval: 1.6, 3.4) and 15.6% (95%

confidence interval: 13.1, 18.4), respectively. Dashed lines, 95% confidence.

Source: from Rebora et al., 2010.

Page 16 of 19

John Wiley & Sons


Figure 1. OS in 102 consecutive CML patients who received first-line imatinib treatment. Numbers on the X axis represent patients at risk. (+): censored patients.

Source: from Viganò et al., 2014.

60x45mm (600 x 600 DPI)

Page 17 of 19

John Wiley & Sons


Figure 2. Estimated cumulative relative survival of chronic myeloid leukemia (CML) patients by period of diagnosis (1970–1984 vs. 1985–1995), Sweden, 1970–1995. Fifteen-year survival figures were 2.4% (95% confidence interval: 1.6, 3.4) and 15.6% (95% confidence interval: 13.1, 18.4), respectively. Dashed lines,

95% confidence. Source: from Rebora et al., 2010.

77x74mm (600 x 600 DPI)

Page 18 of 19

John Wiley & Sons


Table I. Comparison of CCyR rates in different types of studies on CML patients receiving

first line imatinib treatment.

Author Type of study

Year of publication

Country Number of patients

studied % CCyR at/by 12

months

Viganó et al.[8] Single center

2014 Italy 102 83 (at)

Cerrano et al.[30]

Single center

2013 Italy 91 86 (by)

Kantarjian et al.[17]

Registrative 2010 Worldwide 260 72 (by)

Saglio et al.[18] Registrative 2010 Worldwide 283 65 (by)

Zackova et al.[25]

Regional registry

2011

Czech Republic

152

65 (at)

Lucas et al.[29] Regional registry

2008 UK 62 41 (at)

Durosinmi* Single center

2014 Nigeria 151 18 (at)

*Personal communication.

Page 19 of 19

John Wiley & Sons


Documents

How I treat newly diagnosed chronic myeloid leukemia in 2015