Imatinib has quickly and decisively become the initial therapy of choice for chronic myelogenous leukemia (CML) in chronic phase, transplant considerations notwithstanding. Imatinib, as the prototype Abl kinase inhibitor for Philadelphia chromosome positive leukemia, has indeed set a formidable standard to which subsequent Abl kinase inhibitors are compared regarding efficacy and tolerability. However, advances have continued, and the landscape has continued to evolve. What will we settle on as the best initial therapy for CML? Will imatinib be displaced by novel agents developed for imatinib resistance/intolerance? How can we best use the agents we now have available, given the current amount of data for each? And perhaps most challenging, with multiple options with similar benefits, how can one decide?
What is the best choice of initial therapy?
First and foremost, imatinib's efficacy in newly diagnosed CML deftly surpassed interferon, with nearly all patients establishing hematologic response and a clear majority cytogenetic response, both major and complete . Resistance and loss of response, as well as intolerance, are recognized problems and define a sizeable minority over time in need of other therapy. However, most reassuring is the kinetics of resistance after primary imatinib exposure in chronic phase CML: a 5% chance per year of loss of response and 2% chance of progression over the first several years on imatinib, followed by falling rates of progression events and eventual reduction to near zero percent . This is contrary to potential forecasts of increasing resistance over time, especially in light of identification of kinase domain mutations as a lead culprit. Additional factors strengthening the argument to continue to choose standard imatinib as primary therapy for chronic phase CML are: the lack of apparent diminution in transplant outcome in patients who have received kinase inhibitors; the ability of imatinib response to reverse poorer outcomes expected with high (Sokal) risk disease; and the rarity of sudden transformation to advanced disease in the setting of imatinib response. Such factors give us the luxury of time after diagnosis to ‘navigate’ with patients through a therapeutic trial to assess tolerability and response at landmark time points, explore alternative options including a search for transplant donors, while allowing the disease to declare itself and mandate which path may be required.
Should imatinib be used differently at diagnosis, or should newer agents be incorporated?
Despite the high bar set by early response to imatinib, rapid investigation into more intense regimens given at diagnosis was pursued, with combinations of imatinib and traditional agents (interferon and cytarabine) as well as high-dose imatinib. Combination therapy in early trials proved too fraught with toxicity issues, leading to reduction or discontinuation of the added agent; clear benefit could not be ascertained. With a more predictable and acceptable toxicity profile, higher dose imatinib therapy persisted as the best challenge to standard imatinib to improve response. Early data in single arm studies comparing standard dose with high dose (800 mg/day) were encouraging, with gains in rapidity and proportion of patients achieving complete cytogenetic response . With longer follow-up, initial gains were diluted by recognition that standard dose imatinib response, whereas slower than escalated dose, over time ‘caught up’ and ultimate numbers of patients in cytogenetic remission were similar. With further analysis it was demonstrated, however, that high dose imatinib was associated with enhanced progression-free survival – perhaps the most important gain to be made from augmentation of initial therapy in chronic phase CML in light of how efficacious standard imatinib is. Randomized studies to date of 400 versus 800 mg imatinib  and additional study into the advantage of augmented therapy at diagnosis, [focused on initiation at the intermediate dose of 600 mg, and aggressive therapy escalation (including 800 mg imatinib and imatinib/cyatarabine combination) for suboptimal response [4•]] have demonstrated more rapid complete cytogenetic remission rates for high-dose imatinib, yet similar major molecular response at the 12-month mark.
The link between rapidity of response and progression-free survival, coupled with the notion that resistance in CML declares itself early in the course of treatment, and (early) complete cytogenetic response representing a ‘safe haven’ with increased protection against resistance has continued to support the quest to prove something superior to standard dose imatinib in de-novo chronic phase patients. The field of choices now has widened to include not only high-dose imatinib, but also dasatinib and nilotinib, the ‘second-generation’ Abl kinase inhibitors currently approved for imatinib resistance and intolerance, but of course aiming for the potential to displace imatinib as optimal initial therapy. Initial single-arm studies of second-generation agents used at diagnosis [5,6] also show increased rate and proportion of patients achieving complete cytogenetic response, beyond that seen with high-dose imatinib. Improvement in the rate of timely molecular response – major molecular response (reduction in transcripts 3 log-fold or greater below baseline) at the optimal time point of 12 months, as concluded from initial standard dose imatinib studies – is a primary endpoint in comparative trials utilizing high-dose imatinib and is being scrutinized in comparison of single arm trial experience with high-dose imatinib, dasatinib, and nilotinib. To date, data seem to suggest a so-called ‘ceiling effect’ with improvements in early molecular response, but lack of significant difference between standard and high-dose imatinib at the 12-month time point ; improvements with dasatinib or nilotinib [5,6] appear generally similar to high-dose imatinib. It may be thus that we can improve rapidity of cytogenetic and molecular response early and only to a certain degree, and that such improvement is suggested to protect against progression events; further, significant differences in outcome with augmented initial therapy may require longer follow-up to determine.
When is a change in kinase inhibitor therapy indicated?
Assuming the most common scenario of chronic phase CML, treated with standard imatinib (400 mg/day) and leaving aside the issue of intolerance, tracking patients' response currently should involve the proper type of testing (hematologic, cytogenetic, or molecular, or combinations) at landmark time points and categorization of response as optimal, suboptimal, or treatment failure. Action options for each aforementioned category are suggested by guidelines produced by entities such as the National Comprehensive Cancer Network (NCCN)  and the European Leukemia Net (ELN)  (Table 1). In the setting of failure of standard dose imatinib, defined as hematologic or cytogenetic relapse as well as lack of hematologic response after 3 months' treatment, lack of cytogenetic response after 6 months, or lack of major cytogenetic response after 12 months, patients should generally be switched off imatinib, as dose escalation (to 800 mg daily) is less effective at salvaging response and does not provide as durable a response overall [9••]. Smaller incremental change (escalation from 600 to 800 mg) is even less effective and responses as well are less durable.
The category of suboptimal response is fraught with the difficulties of trying to separate out patients with continued, yet protracted, potential for target responses (‘slow responders’) from those with truly inadequate response (and thus high risk for relapse or progression), as well as the multiplicity of current options (dose escalation of imatinib, nilotinib, dasatinib, as well as simple observation over a greater length of time). Clinical trials planned and launched for this category have been difficult and some even halted due to slow accrual. Ideally, further diagnostics to help clarify patients' risk of progression, potential to develop resistance, or actual identification of relevant kinase domain mutations or other mechanisms prior to clinical relapse would be ideal to guide management of ‘high risk’ cases, either empirically at presentation or at identification of suboptimal response. Analyses of patients considered ‘suboptimal’ early in disease course when landmark responses are in the realm of cytogenetics – during the first year of treatment – suggest that their fate is quite inferior and similar to cases considered ‘failure’ [10•]. After the first year, when molecular response decides between ‘optimal’ and ‘suboptimal’, true differences remain between ‘suboptimal’ and ‘failure’ cases, suggesting that molecular ‘slow responders’ exist, but true cytogenetic ‘slow responders’ are rare, and inferior cytogenetic response warrants intervention.
Progressive disease, that is, proliferation of CML leading to cytogenetic or hematologic relapse, and for certain transition from chronic phase to accelerated phase or blast crisis, is the most clear-cut situation in which change in therapy is needed, and more detailed examination into mechanisms of resistance may be helpful. Earlier intervention, at the time of cytogenetic rather than combined hematologic and cytogenetic relapse, was studied regarding salvage with dasatinib and treatment at the time of cytogenetic relapse led to superior response and moreover better survival free of progression . This suggests that progressive proliferation within the chronic phase in the face of imatinib may be associated with increasing clonal instability; the response rate differences between salvage of patients with resistance within chronic phase versus those who progress to accelerated or blast phase disease speak to the fact that such transforming events are even less amenable to salvage with alternate tyrosine kinase inhibitors (TKIs) and identify closure of a window of opportunity to contain and manage resistance optimally.
Which salvage agent for which patient in what setting?
Rare in the treatment of cancer do we see the situation at present in the management of CML patients, in which primary therapy with imatinib is successful in the short and longer term for the majority of cases, and thus salvage is not needed. For the minority of cases of primary and secondary failure as well as those with intolerance in which salvage is necessary, two approved options with a high degree of efficacy exist. Dasatinib and nilotinib were both studied for the salvage of Philadelphia positive leukemia; dasatinib was developed for other purposes, but recognized as a potent Abl inhibitor and was approved first; nilotinib was developed and derived from imatinib for the purpose of treating identified, prominent mechanisms of resistance (Abl kinase domain mutations) and was approved second. Dasatinib is approved for all phases of CML (chronic phase, accelerated phase, lymphoid and myeloid blast crisis) and Philadelphia positive acute lymphoid leukemia (ALL); nilotinib is currently approved for chronic and accelerated phase CML. Response rates in pivotal trials with median follow-up are shown in Table 2 [12,13•]. Ideally, randomized trials between the two agents could be performed to clarify differences in efficacy and toxicity, but are unlikely to ever occur. With regard to comparative trials of imatinib dose escalation versus an alternative TKI for ‘failure’ cases, data have been generated for dasatinib only [9••], despite the fact that both dasatinib and nilotinib are accepted and available as alternatives to dose escalation for imatinib failure.
In focusing on chronic phase CML, in which the majority population at risk and in need of alternate therapies lies, studied populations were similar, but not equal, in the trials of dasatinib and nilotinib, and a ‘quick look’ at the response data would suggest that the drugs are fairly similar. In attempts to differentiate the two agents, toxicity comparisons are often made as well as focus placed on the resistance profile of studied patients, namely within the subgroup of patients with known kinase domain mutations (Table 3) [12,13•,14•]. Perhaps the most notable point is that in the setting of imatinib resistance identified clinically, screening for kinase domain mutations is unrevealing (none found) in 50% of cases; this would leave any decision between dasatinib and nilotinib up to a review of toxicity potential and preference. In the 50% or so of cases with mutations at the time of switch to ‘second line’ therapy, there are several points to note. First, the most important role of screening is to identify/‘rule out’ presence of the T315I mutation, not uncommon [∼10% of mutation (+) cases] and not amenable based on in-vitro and clinical data to continue imatinib or switch to nilotinib or dasatinib; second, identifying mutations in the ‘p-loop’ (positions 248–256) and other select mutations (positions 299, 317, and 359) is useful, as preclinical and clinical response data relevant to these select mutations can guide the choice between nilotinib and dasatinib; and last, the majority of mutations seen in such cases are not associated with different clinical response rates in comparing data from nilotinib and dasatinib studies, and response was not statistically different in both agents' phase II studies when comparing patients with or without mutations at time of change.
It will be perhaps more important to understand the role of select mutations such as the T315I and patterns of resistance that develop after continued selection pressure from sequential kinase inhibitor therapy. Noting the presence of ‘imatinib resistant’ kinase mutations in advanced phase patients prior to imatinib exposure  clearly suggests that genesis of mutations is part of the natural evolution of CML and related to clonal instability, increasingly prominent in advanced phase, and not solely due to selection pressure from TKI exposure. It is likely that we are thus ‘fueling a fire’ that had already begun, either occult ‘embers’ or overt flames from dominant clones present at the time resistance is evident.
Regarding the selection of nilotinib or dasatinib for patients on the basis of potential toxicity and comorbidites, careful review of both agents' profiles will generate a short list, in which ‘avoidance’ could be proposed; it would be exceedingly rare for a patient to be categorically excluded from having a therapeutic trial of either agent due to a preexisting condition. For nilotinib, potential pancreatic and, to a lesser degree, hepatic toxicity may warrant avoidance in select patients; for dasatinib, pleural/pericardial fluid retention toxicity and, to a lesser degree, bleeding risk may warrant similar avoidance. Both agents have a fair degree of myelosuppression, with dasatinib's current (100 mg daily) approved dose improved over its initial (70 mg b.i.d.) approved dose [16•], but still somewhat more likely than nilotinib to cause high grade myelosuppression. Although obviously relevant to patient care and raising the possibility of treatment morbidity, myelosuppression is expected and normal in advanced phase patients and as well in chronic phase patients, is linked to activity and clinical response, and should thus be anticipated and managed accordingly.
The tyrosine kinase inhibitors as a class have effect on the QT duration, and nilotinib's label includes stricter screening and monitoring requirements; review of the incidence in multiple studies [12,13•] shows that QT prolongation may occur with dasatinib and nilotinib at very low frequency. For patients with preexisting anomalies, those on other therapies affecting the QT and those prone to electrolyte fluctuations with potential to exacerbate such toxicity, at a minimum vigilance and in select cases avoidance would be recommended for nilotinib or potentially all TKIs.
When should transplant evaluation/discussion commence?
Again, transformed CML after imatinib failure represents a lost opportunity to turn to a potentially curative, but significantly diminished use option, allografting. Evaluation for potential donors, via sibling typing or proceeding on to initial unrelated donor search for patients in whom allografting represents acceptable risk, both adds information to guide decision-making regarding response to nontransplant therapy and acceptance of toxicity and reduces potential risk of progression during the ‘lead-time’ of stem cell transplantation evaluation. Patients, needing to hear about all options, can be counseled about risk, timing, and logistics of potential transplant in general terms. This can be accomplished while ‘waiting’ the 1–1.5 years for initial imatinib response to be determined – often perceived as long and at or beyond historic interferon era timeframes for optimal timing of an allograft for CML, but quite reasonable for most patients. As mentioned earlier, TKIs – in addition to their high response rate and durability – have given us the luxury of time for treatment and decision-making in CML, time that needs to be wisely comanaged with the patient.
If the development of imatinib eloquently proved Abl kinase inhibition to be a rational and highly effective approach for managing CML, the subsequent arrival of dasatinib and nilotinib have reinforced the centrality of Abl inhibition and taken options for patients to another significantly higher level. It may be the case that for a majority of patients diagnosed in early chronic phase, imatinib therapy at standard doses is entirely sufficient to manage the disease; it is clear, however, that for others this is not enough. How we use these multiple options during the course of CML continues to evolve, and the quest for optimization and perfection of response and outcome continues, inspired and driven by the revolutionary change kinase inhibition has brought to this disease.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 151).
1 Hochhaus A, Drucker BJ, Larson RA, et al. IRIS 6-year follow-up: sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib [abstract #25]. Blood 2007; 110.
2 Aoki E, Kantarjian H, O'Brien S, et al. High-dose imatinib mesylate treatment in patients (pts) with untreated early chronic phase (CP) chronic myeloid leukemia [abstract #6365]. J Clin Oncol 2006; 20.
3 Cortes JE, Baccarani M, Guilhot F, et al. First report of the TOPS study: a randomized phase III trial of 400 mg vs. 800 mg imatinib in patients with newly diagnosed, previously untreated CML in chronic phase using molecular endpoints [abstract #402]. Haematologica 2008; 93.
4• Hughes TP, Branford S, White DL, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008; 112:3965–3973.
5 Cortes J, O'Brien S, Jabbour E, et al. Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP) [abstract #29]. Blood 2007; 110.
6 Cortes J, O'Brien S, Jones D, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP) [abstract #30]. Blood 2007; 110.
7 National Comprehensive Cancer Network. NCCN: clinical practice guidelines in oncology. Chronic myelogenous leukemia. Version 3, 2008.
8 Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood 2006; 108:1809–1820.
9•• Marin D, Milojkovic D, Olavarria E, et al. European Leukemia Net criteria for failure or sub-optimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008; 112:4437–4444. This study analyzes the outcome of patients with CML on imatinib characterized as suboptimal and failure by Leukemia Net guidelines and illustrates that outcomes may be similar.
10• Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase-II trial. Blood 2007; 109:5143–5150. This paper reports on the only study randomizing imatinib failure patients to either higher dose imatinib or salvage with an alternative kinase inhibitor (here, dasatinib).
11 Kantarjian HM, Quintas-Cardama A, O'Brien S, et al. Importance of early intervention with dasatinib at cytogenetic rather than hematologic resistance to imatinib [abstract #1036]. Blood 2007; 110.
12 Mauro MJ, Baccarani M, Cervantes F, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C) [abstract #7009]. J Clin Oncol 2008; 26.
13• Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007; 110:3540–3546. This study reports on the efficacy of nilotinib in the treatment of imatinib-resistant or intolerant chronic phase CML.
14• De Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol 2008; 141:745–747.
15 Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005; 106:2128–2137.
16• Shah NP, Kantarjian HM, Kim D-W, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26:3204–3212. This study reports on a ‘dose optimization’ study of dasatinib in chronic phase CML patients and the rationale behind reduction in the recommended dose to 100 mg daily.
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