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 been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/ajh.23887
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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 2
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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 3
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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 4
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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] .
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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.
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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 6
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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 7
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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.lmcfrance.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 8
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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 RTPCR, 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, 9
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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% 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. 14
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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.
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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. Fifteenyear 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.
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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)
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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)
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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.
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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 been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/ajh.23887
American Journal of Hematology
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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 2
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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 3
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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 4
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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] .
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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.
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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 6
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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 7
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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.lmcfrance.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 8
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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 RTPCR, 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, 9
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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% 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. 14
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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.
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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. Fifteenyear 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.
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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)
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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)
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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.
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