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NCCN and ELN: What do the guidelines tell us?
Best Practice & Research Clinical Haematology 29 (2016) 264e270
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
NCCN and ELN: What do the guidelines tell us? Kendra Sweet*, Javier Pinilla-Ibarz Moffitt Cancer Center, Tampa, FL, United States
a b s t r a c t Keywords: Chronic Myeloid Leukemia BCR-ABL Tyrosine kinase inhibitors NCCN ELN
The prognosis for patients with Chronic Myeloid Leukemia is vastly different in 2016 compared to 20 years ago, and this is due to the development of BCR-ABL tyrosine kinase inhibitors (TKIs). As newer, more potent, TKIs have been developed and approved over the past 15 years, the decision about which drug to use as first line therapy, and when to switch treatment in particular patients has become more complicated. The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) have developed treatment and monitoring guidelines to aide in the management of these patients. The guidelines were developed by two groups of CML experts and recommendations are based on available data and expert opinion. With adherence to the recommendations proposed by the NCCN and ELN, we can expect to continue to see excellent outcomes for our patients with CML. © 2016 Elsevier Ltd. All rights reserved.
Overview Expected outcomes for patients with Chronic Myeloid Leukemia are vastly different in 2016 compared to what they were in the 1990's and early 2000's. Whereas previously responses to CML directed therapy were assessed on a hematologic and cytogenetic level, in the current era of highly effective BCR-ABL tyrosine kinase inhibitors successful treatment responses are assessed using sensitive molecular testing methods including quantitative polymerase chain reaction (Q-PCR) to quantify BCR-ABL transcript levels.
* Corresponding author. 12902 Magnolia Dr., FOB3-Heme, Tampa, FL 33612, United States. E-mail address: Kendra.Sweet@moffitt.org (K. Sweet). http://dx.doi.org/10.1016/j.beha.2016.10.016 1521-6926/© 2016 Elsevier Ltd. All rights reserved.
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The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) are two of the predominate international committees which have designed evidence based guidelines for the treatment and management of CML in chronic (CP), accelerated (AP) and blast (BP) phases of the disease. The NCCN CML committee is comprised of a group of CML experts from each of the 26 NCCN Member Institutions. The guidelines are evidence based and result from the author's analysis of published data as well as their views of currently accepted treatment approaches. The ELN CML panel is made up of 32 experts from Europe, America and the Asian-Pacific region who have come together on multiple occasions to discuss pertinent questions related to the most up-todate literature regarding management of CML. Their recommendations are the result of consensus from the entire group in regard to the most evidence based treatment and management of CML. Here we discuss the NCCN and ELN guidelines for all phases of CML as well as some of the data that has been analyzed in order to develop these recommendations. Diagnosis and first line treatment Both the ELN and the NCCN recommend a complete workup at the time of diagnosis including a history and physical with accurate measurement of the patient's spleen. A complete blood count with a differential along with a bone marrow biopsy and aspirate to determine the blast and basophil percentage are essential components for determining the phase of CML. G-banding cytogenetics and QPCR to measure BCR-ABL transcripts reported on the International Scale are also necessary at the time of diagnosis. This baseline information is needed in order to determine a patient's risk score which could be done using the Sokal or Hasford Score per the NCCN guidelines, or the Sokal, Euro or EUTOS score per the ELN guidelines [1,2]. All of the above data should be analyzed together in order to choose the most appropriate first line treatment for a patient. In 2016, all available CML treatment recommendations suggest that first line therapy should be a BCR-ABL tyrosine kinase inhibitor, with very few exceptions. Currently, there are three TKIs approved in the first line setting including imatinib (first generation), dasatinib and nilotinib (second generation) [3e5]. Neither the ENL nor the NCCN specifically recommend one TKI over the other, however the NCCN guidelines suggest that those with intermediate- or high-risk Sokal or Hasford scores may fare better with a second generation TKI rather than imatinib [1]. The IRIS Study showed a significant increase in cytogenetic response rates in imatinib treated patients compared with those receiving Interferon and low-dose Cytarabine [3], however due to the high rate of cross-over from IFN to imatinib, the study results did not show a survival benefit after 1 year [6]. A significant survival benefit was demonstrated with imatinib when compared with historical controls who were treated with IFN [7]. Long-term data from the IRIS trial indicate a CCyR rate of 82% with a median follow-up of 60 months with only 7% of patients progressing to AP or BP CML. At the same time period the overall survival (OS) was 89% [8]. Dasatinib 100 mg once daily was compared with imatinib 400 mg once daily in 519 newly diagnosed CML patients in the DASISION trial and after a minimum follow-up of 12 months, the confirmed rates of CCyR and MMR were higher in the dasatinib arm compared with the imatinib arm (CCyR 77% vs. 66% and MMR 46% vs. 28%). The safety and tolerability was similar between both drugs [4]. With 5years of follow-up, dasatinib has demonstrated faster and deeper cytogenetic and molecular responses compared with imatinib. Dasatinib also resulted in higher rates of CCyR (83% vs. 78%; p ¼ 0.187), MMR (76% vs. 64%; p ¼ 0.002) and MR4.5 (42% vs. 33%; p ¼ 0.025) at 5 years. Furthermore, progression to AP/ BP CML were lower in dasatinib treated patients (4.6% vs. 7.3%) [9]. When stratifying patients based on Hasford score, dasatinib induced more MMRs than imatinib in each risk group (low 73% vs. 56%; intermediate 61% vs. 50%; high 57% vs. 38%) [9]. Nilotinib 300 mg twice daily and nilotinib 400 mg twice daily were compared to imatinib 400 mg daily in newly diagnosed CML patients in the ENESTnd trial. The 12-month analysis indicated higher rates of CCyR and MMR in nilotinib treated patients. CCyR was achieved at 12 months in 80%, 78% and 65% of nilotinib 300 mg, nilotinib 400 mg and imatinib patients respectively. MMR was achieved at 12 months in 44%, 43% and 22% of nilotinib 300 mg, nilotinib 400 mg and imatinib patients respectively. These superior CCyR and MMR rates were seen with nilotinib across all Sokal risk groups. Moreover, the rate of transformation to advanced phase CML was 4% in the imatinib arm compared with <1% in either
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nilotinib arm [5]. The lowest rate of discontinuation due to adverse events was seen in the nilotinib 300 mg twice daily arm, and therefore this is the dose that was granted FDA approval for previously untreated chronic phase CML patients. After 5-years of follow up, MMR was achieved in 77%, 77% and 60% of nilotinib 300 mg, nilotinib 400 mg and imatinib treated patients respectively. MR4.5 was achieved in 54%, 52% and 31% of nilotinib 300 mg, nilotinib 400 mg and imatinib patients respectively. Similar to what was seen with dasatinib, nilotinib demonstrated deeper and faster molecular responses when compared with imatinib [10]. In spite of the superior rates of cytogenetic and molecular responses in newly diagnosed patients treated with second generation TKIs, thus far, no overall survival benefit has been demonstrated. The 5year overall survival on the DASISION trial was 91% with dasatinib and 90% with imatinib, and this difference was not statistically significant. ENESTnd produced 4-year overall survival of 94.3% (nilotinib 300 mg BID) 96.7% (nilotinib 400 mg BID) and 93.3% (imatinib), and again, these differences did not reach statistical significance. After five years of the DASISION trial, 61% of dasatinib treated patients and 63% of nilotinib treated patient remained on their study treatment. After five years of the ENESTnd trial 60% of nilotinib 300 mg BID, 62% of nilotinib 400 mg BID and 50% of imatinib patients remained on their core treatment. Therefore, imatinib, dasatinib and nilotinib all remain viable options for treatment of newly diagnosed CML patients [4,5,9,10]. Monitoring recommendations The recommendations for monitoring patients with CML differ slightly between the ELN and the NCCN. Both committees agree that monitoring should be done at regular intervals using G-banding cytogenetics on bone marrow aspirate samples (FISH on the peripheral blood is an acceptable alternative in specific situations) as well as Q PCR to measure the BCR-ABL1 transcript levels. The PCR results must be reported using the standardized International Scale otherwise they are not able to be compared against the recommended treatment milestones [11]. The ELN recommends monitoring by cytogenetics at diagnosis, 3, 6 and 12 months after beginning TKI therapy until a patient has achieved CCyR. Once CCyR has been attained, cytogenetics should be monitored annually and FISH for BCR-ABL in the peripheral blood is an acceptable alternative to standard cytogenetics in the bone marrow. PCR monitoring is recommended every 3 months until a patient achieves MMR at which point the frequency of PCR monitoring may decrease to every 3e6 months [2]. The NCCN monitoring guidelines recommend cytogenetics at diagnosis for all patients, and at 3 and 6 months if reliable PCR reported on the International Scale is not available. If a patient has not achieved CCyR or MMR by 12 months, a bone marrow biopsy with cytogenetics is recommended at this time point. Once a patient has achieved CCyR, cytogenetics are no longer needed per the NCCN unless the patient experiences a 1-log increase in BCR-ABL transcript levels by PCR in the absence of MMR. QPCR for BCR-ABL is recommended at diagnosis and should continue every 3 months until 2 years after the patients has achieved CCyR. At that point the frequency may decrease to every 3e6 months. If a 1log increase in BCR-ABL transcripts is noted on routine monitoring, yet the patient maintains MMR, the PCR should be rechecked in 1e3 months [1]. PCR results may vary slightly over time due in part to the technical methods used in testing; therefore minor fluctuations in BCR-ABL transcript levels should not reflexively trigger repeat testing nor be the reason for changing therapy. However, significant increases of 1-log should be followed up closely [1,2]. 3-month assessment The first response assessment that may alter the course of treatment for a patient takes placed after 3 months on TKI therapy. The optimal response in all patients according to both the ELN and the NCCN is a PCR value of <10% IS at this 3 month mark. If PCR reported on the International Scale is not available or not reliable, a bone marrow biopsy with cytogenetics is indicated. The optimal response is a partial cytogenetic response (PCyR) defined as <35% Philadelphia Chromosome positive metaphases. If these
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milestones have been met, both guideline committees recommend continuation of the current therapy with repeat assessment at 6 months [1,2]. Per the ELN, treatment failure at 3 months is defined as a lack of complete hematologic response (CHR), >95% Philadelphia chromosome positive metaphases or the development of new kinase domain mutations. Therefore, if a patient fails to obtain an optimal response of BCR-ABL <10% but does not meet the specific criteria for failure, they will continue their current treatment. In this situation they fall into the warning category in which more frequent monitoring is recommended [2]. Per the NCCN, BCR-ABL transcripts >10% at 3 months warrants a change in treatment in any patient being treated with imatinib. However, if they are receiving treatment with nilotinib or dasatinib as first line therapy, the decision regarding whether or not a treatment change is indicated is left to the discretion of the treating physician. Regardless of first line therapy, anyone with BCR-ABL >10% at this time point should have a kinase domain mutation analysis (KDMA), and issues such as compliance with daily therapy and drugedrug interactions need to be addressed [1]. The prognostic significance of the 3 month molecular response is well established. Marin and colleagues reported results from a retrospective analysis of 282 CP-CML patients who received imatinib as first line therapy which indicated that those with BCR-ABL <9.84% at 3 months had significantly higher 8-year OS (93.3% vs. 56.9%), PFS (92.8% vs. 57%) and EFS (65% vs. 6.9%) compared to those with BCR-ABL >9.84% [12]. Hanfstein et al. analyzed 1303 CP-CML patients being treated with first-line imatinib from the CML IV study. In this study patients who failed to achieve a PCyR (approximately equivalent to BCR-ABL <10% IS) at 3 months had a 95% 5-year OS compared to 87% in patients with PCyR (p < 0.0001). Additionally the 5-year PFS in those with PCyR at 3 months was 92% vs. 87% in patients without PCyR at the same time period (p ¼ 0.037) [13]. Data published by Branford and colleagues further supports this, while showing the 4-year OS was 97% for patients with <10% BCR-ABL at the three month evaluation, versus 87% for those with >10%. Moreover, their data indicate that 88% of patients with <10% BCR-ABL at three months achieved MMR while only 41% of those with BCR-ABL >10% met this milestone. Interestingly, they found that of the patients who failed to meet this threemonth benchmark, the ones who ultimately had worse outcomes, were those in which the halvingtime of the BCR-ABL was >76 days. This suggests that the kinetics of the decline in BCR-ABL more so than the transcript level itself has prognostic significance [14]. Landmark analyses from the DASISION and ENESTnd trials both demonstrated that early molecular response has prognostic significance irrespective of first line therapy [15e17]. Despite consistent data suggesting inferior outcomes in patients who have BCR-ABL >10% at 3 months, neither the NCCN nor the ELN definitively recommend changing treatment at this time point. The one exception to this is the NCCN recommendation to change treatment if the first line TKI is imatinib [1,2]. This is due to the lack of data suggesting that outcomes are improved for patients who switch treatment at this time point. Furthermore, all of the data showing the prognostic impact of the 3-month assessment is retrospective, and was not part of a pre-planned analysis [12,13,15e17]. 6-month assessment By 6 months on therapy, the expectation of the NCCN is a BCR-ABL transcript level of <10% IS using QPCR on the peripheral blood just as it is at the 3-month evaluation. Irrespective of first line TKI, if a patient's BCR-ABL is >10% after 6 months, the guidelines recommend changing treatment. A KDMA as well as an assessment of patient compliance and drugedrug interactions should also take place. This is an appropriate time to consider a transplant evaluation in eligible patients as well. On the other hand, if the results of the PCR are <10%, patients are considered to be meeting the desired milestones, and should continue their current treatment [1]. The ELN has stricter guidelines at this time point, with an optimal response being defined as BCRABL transcripts <1% IS. Failure is defined as a value > 10% and anything between 1 and 10% is considered a warning [2]. Data published by Hanfstein et al. demonstrated a statistically significant improvement in 5-year overall survival in imatinib treated patients with <1% BCR-ABL transcripts at 6 months compared with those who remained >1% (97% vs. 87%, p < 0.001) [13]. A number of trials have been conducted looking at the impact of switching therapy or escalating doses of current therapy in patients with suboptimal responses to imatinib or nilotinib, and the data suggest there is a subset of patients
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who are able to achieve deeper levels of response after intensifying treatment [18,19]. For these reasons, the NCCN and the ELN recommend treatment changes for patients with >10% BCR-ABL transcripts at 6 months. 12-month assessment All patients with CP-CML should be evaluated every 3 months. At the 12 month evaluation, the NCCN considers a CCyR to be an adequate response to treatment. Therefore, in patients without a documented CCyR or MMR a bone marrow aspirate and biopsy with cytogenetics should be done to determine the cytogenetic response. It is the opinion of the guideline committee that FISH has not been adequately studied in CML and therefore should not be used as a surrogate for a bone marrow biopsy with cytogenetics. The absence of MMR in the setting of CCyR should not be considered treatment failure according to the NCCN [1]. This recommendation is based on data suggesting that early cytogenetic response is a significant prognostic factor in patients with CML, irrespective of their TKI. A study published by Jabbour and colleagues demonstrated significantly better EFS and OS in patients who achieved CCyR at 12 months (98% and 99%) compared with those who did not have CCyR at the same time point (67% and 94%) [20]. The ELN considers MMR to be an optimal response after 12 months on TKIs. Those with BCR-ABL transcripts between 0.1% and 1% are in the warning category and anything >1% or the absence of CCyR is considered treatment failure [2]. Although the definition of treatment failure is the same according to the NCCN and the ELN, the ELN considers a deeper level of molecular response to be optimal. The 5-year follow up from the IRIS trial found that no patients who had achieved MMR at 12 months progressed to accelerated or blast phase CML. Those with MMR at 12 months had a 24 month PFS of 100% compared with 95% in patients with CCyR but no MMR at 12 months [8]. Others have suggested that the absence of a 3-log reduction or MMR at any point after achieving a CCyR correlates with a significantly shorter PFS [21]. However, Hehlman et al. published data suggesting that although 3-year PFS and OS are better in patients with MMR at 12 months compared to those without MMR, further stratification of the subjects found no difference in PFS or OS in patients with MMR at 12 months compared with the group of patients whose transcripts were 0.1%e1%. The inferior outcomes were seen in those with BCR-ABL >1% at 12 months [22]. Additional studies have failed to show an improvement in PFS or OS in patients achieving MMR at 12 or 18 months compared with those patients achieving CCyR at 12 months [23,24]. Taken together these data suggest that prognostic significance is clear with CCyR at 12 months, however there is still debate surrounding the prognostic significance of MMR at the same time point. Advanced phase CML In the current era of TKI therapy for CML, progression to accelerated or blast phase CML occurs in <10% of patients who have been diagnosed in chronic phase (CP) [8e10]. In those patients who do progress to an advanced phase of CML, the recommended management differs from that of CP-CML. In AP-CML, the NCCN strongly encourages patients to be treated at a specialized center. All patients should have a KDMA and the choice of TKI should be dependent on the results of the KDMA as well as the patient's treatment history. An evaluation and donor search for an allogeneic stem cell transplant is appropriate in patients with AP-CML, however depending on the response to treatment, transplant may or may not be necessary [1]. According to the ELN, the management of AP-CML differs depending on whether a patient was diagnosed in AP or if they progressed from prior CP-CML. In those patients diagnosed in AP, the ELN recommends treatment with imatinib or dasatinib as first line therapy. They encourage a donor search for possible allogeneic stem cell transplant, but similar to the NCCN, transplant is not recommended in all patients. On the other hand, if a patient has progressed to AP-CML from prior CP, any TKI is recommended based on results of a KDMA as well as the patient's treatment history. In this setting, the ELN recommends allogeneic stem cell transplant in eligible patients with suitable donors [2]. Outcomes for patients with BP-CML have historically been very poor with the only curative option coming from an allogeneic stem cell transplant [25e27]. For this reason, the NCCN strongly
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recommends treatment at a specialized center. All patients should have a KDMA at the time of BP-CML diagnosis as this will help guide future treatment decisions. BP-CML may be lymphoid or myeloid and this distinction is an essential component of treatment decision making. Per the NCCN, lymphoid BP should be treated with either a TKI alone or an acute lymphoblastic leukemia-type induction regimen in combination with a TKI. Regardless of whether treatment is with a TKI or TKI plus induction, eligible patients must undergo an allogeneic stem cell transplant. Similarly, for those with myeloid BP, the recommended treatment includes either a single agent TKI or an acute myeloid leukemia-type induction regimen in combination with a TKI. Again, in all eligible patients, allogeneic stem cell transplant is considered the definitive treatment in these patients. The risk of post-transplant relapse is high for patients who have been transplanted for AP or BP-CML. For this reason, the NCCN recommends that post-transplant TKIs should be considered for at least one year in all patients who achieve a remission [1]. There is data to support the use of imatinib in this setting, however in patients who have already failed imatinib, another TKI should be used [1,28]. As with AP-CML, the ELN recommendations for management of BP-CML distinguish between those diagnosed in BP vs. those diagnosed in CP who have later progressed to BP-CML. Treatment with imatinib or dasatinib is recommended for patients diagnosed in BP, however any TKI is appropriate for those whose disease progressed to BP-CML. As with AP-CML, the choice of TKI should be based on the results of a KDMA as well as the patient's treatment history. In both scenarios of BP-CML, the ELN recommends allogeneic stem cell transplant for all eligible patients [2]. The primary goal of treatment prior to transplant is to return to CP-CML as this leads to the best potential outcomes after transplant [27]. Summary The evolution of effective therapeutic options in CML over the past 15 years has been dramatic, and with improved treatments come new recommendations for proper patient management. The NCCN and ELN have both published guidelines for treating patients with CP-, AP- and BP-CML. The recommended milestones at each time point in a patient's therapy are based on published data suggesting improvement in PFS or OS in patients meeting those milestones. There are minor differences in the recommendations set forth by the two committees, however the proposed definitions of treatment failure are very similar [1,2]. The projected outcomes for the vast majority of patients diagnosed with CP-CML are promising, with very few patients progressing to AP- or BP-CML. Available data suggest that patients who progress tend to do so early in their treatment course, making stringent monitoring all the more essential in the critical early months to years on TKIs [9,10,29]. Recognizing patients who are failing treatment, testing for mutations that may be responsible for resistance, and discussing issues such as potential drug interactions and compliance with therapy are necessary components for achieving optimal outcomes in patients with CML. Both sets of guidelines provide clear recommendations for when these additional tests and interventions are indicated. This is becoming all the more important now that imatinib has become generic and its use as a first line TKI is likely to increase in the coming years. Although many of these patients will respond well, this will increase the number of patients who fail to meet the early milestones, and therefore require a change in their treatment. With adherence to treatment guidelines, and adequate TKI side effect management, we can continue to see the excellent long-term survival we have come to expect in patients with CP-CML. Conflict of Interest KS is on the speakers bureau for Novartis, Pfizer and Araid and is a consultant for Novartis and Ariad. JPI is on the speakers bureau for Bristol Myer Squibb and Pfizer and is a consultant for Novartis, Bristol Myer Squibb, Pfizer and Ariad.
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Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
NCCN and ELN: What do the guidelines tell us? Kendra Sweet*, Javier Pinilla-Ibarz Moffitt Cancer Center, Tampa, FL, United States
a b s t r a c t Keywords: Chronic Myeloid Leukemia BCR-ABL Tyrosine kinase inhibitors NCCN ELN
The prognosis for patients with Chronic Myeloid Leukemia is vastly different in 2016 compared to 20 years ago, and this is due to the development of BCR-ABL tyrosine kinase inhibitors (TKIs). As newer, more potent, TKIs have been developed and approved over the past 15 years, the decision about which drug to use as first line therapy, and when to switch treatment in particular patients has become more complicated. The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) have developed treatment and monitoring guidelines to aide in the management of these patients. The guidelines were developed by two groups of CML experts and recommendations are based on available data and expert opinion. With adherence to the recommendations proposed by the NCCN and ELN, we can expect to continue to see excellent outcomes for our patients with CML. © 2016 Elsevier Ltd. All rights reserved.
Overview Expected outcomes for patients with Chronic Myeloid Leukemia are vastly different in 2016 compared to what they were in the 1990's and early 2000's. Whereas previously responses to CML directed therapy were assessed on a hematologic and cytogenetic level, in the current era of highly effective BCR-ABL tyrosine kinase inhibitors successful treatment responses are assessed using sensitive molecular testing methods including quantitative polymerase chain reaction (Q-PCR) to quantify BCR-ABL transcript levels.
* Corresponding author. 12902 Magnolia Dr., FOB3-Heme, Tampa, FL 33612, United States. E-mail address: Kendra.Sweet@moffitt.org (K. Sweet). http://dx.doi.org/10.1016/j.beha.2016.10.016 1521-6926/© 2016 Elsevier Ltd. All rights reserved.
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The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) are two of the predominate international committees which have designed evidence based guidelines for the treatment and management of CML in chronic (CP), accelerated (AP) and blast (BP) phases of the disease. The NCCN CML committee is comprised of a group of CML experts from each of the 26 NCCN Member Institutions. The guidelines are evidence based and result from the author's analysis of published data as well as their views of currently accepted treatment approaches. The ELN CML panel is made up of 32 experts from Europe, America and the Asian-Pacific region who have come together on multiple occasions to discuss pertinent questions related to the most up-todate literature regarding management of CML. Their recommendations are the result of consensus from the entire group in regard to the most evidence based treatment and management of CML. Here we discuss the NCCN and ELN guidelines for all phases of CML as well as some of the data that has been analyzed in order to develop these recommendations. Diagnosis and first line treatment Both the ELN and the NCCN recommend a complete workup at the time of diagnosis including a history and physical with accurate measurement of the patient's spleen. A complete blood count with a differential along with a bone marrow biopsy and aspirate to determine the blast and basophil percentage are essential components for determining the phase of CML. G-banding cytogenetics and QPCR to measure BCR-ABL transcripts reported on the International Scale are also necessary at the time of diagnosis. This baseline information is needed in order to determine a patient's risk score which could be done using the Sokal or Hasford Score per the NCCN guidelines, or the Sokal, Euro or EUTOS score per the ELN guidelines [1,2]. All of the above data should be analyzed together in order to choose the most appropriate first line treatment for a patient. In 2016, all available CML treatment recommendations suggest that first line therapy should be a BCR-ABL tyrosine kinase inhibitor, with very few exceptions. Currently, there are three TKIs approved in the first line setting including imatinib (first generation), dasatinib and nilotinib (second generation) [3e5]. Neither the ENL nor the NCCN specifically recommend one TKI over the other, however the NCCN guidelines suggest that those with intermediate- or high-risk Sokal or Hasford scores may fare better with a second generation TKI rather than imatinib [1]. The IRIS Study showed a significant increase in cytogenetic response rates in imatinib treated patients compared with those receiving Interferon and low-dose Cytarabine [3], however due to the high rate of cross-over from IFN to imatinib, the study results did not show a survival benefit after 1 year [6]. A significant survival benefit was demonstrated with imatinib when compared with historical controls who were treated with IFN [7]. Long-term data from the IRIS trial indicate a CCyR rate of 82% with a median follow-up of 60 months with only 7% of patients progressing to AP or BP CML. At the same time period the overall survival (OS) was 89% [8]. Dasatinib 100 mg once daily was compared with imatinib 400 mg once daily in 519 newly diagnosed CML patients in the DASISION trial and after a minimum follow-up of 12 months, the confirmed rates of CCyR and MMR were higher in the dasatinib arm compared with the imatinib arm (CCyR 77% vs. 66% and MMR 46% vs. 28%). The safety and tolerability was similar between both drugs [4]. With 5years of follow-up, dasatinib has demonstrated faster and deeper cytogenetic and molecular responses compared with imatinib. Dasatinib also resulted in higher rates of CCyR (83% vs. 78%; p ¼ 0.187), MMR (76% vs. 64%; p ¼ 0.002) and MR4.5 (42% vs. 33%; p ¼ 0.025) at 5 years. Furthermore, progression to AP/ BP CML were lower in dasatinib treated patients (4.6% vs. 7.3%) [9]. When stratifying patients based on Hasford score, dasatinib induced more MMRs than imatinib in each risk group (low 73% vs. 56%; intermediate 61% vs. 50%; high 57% vs. 38%) [9]. Nilotinib 300 mg twice daily and nilotinib 400 mg twice daily were compared to imatinib 400 mg daily in newly diagnosed CML patients in the ENESTnd trial. The 12-month analysis indicated higher rates of CCyR and MMR in nilotinib treated patients. CCyR was achieved at 12 months in 80%, 78% and 65% of nilotinib 300 mg, nilotinib 400 mg and imatinib patients respectively. MMR was achieved at 12 months in 44%, 43% and 22% of nilotinib 300 mg, nilotinib 400 mg and imatinib patients respectively. These superior CCyR and MMR rates were seen with nilotinib across all Sokal risk groups. Moreover, the rate of transformation to advanced phase CML was 4% in the imatinib arm compared with <1% in either
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nilotinib arm [5]. The lowest rate of discontinuation due to adverse events was seen in the nilotinib 300 mg twice daily arm, and therefore this is the dose that was granted FDA approval for previously untreated chronic phase CML patients. After 5-years of follow up, MMR was achieved in 77%, 77% and 60% of nilotinib 300 mg, nilotinib 400 mg and imatinib treated patients respectively. MR4.5 was achieved in 54%, 52% and 31% of nilotinib 300 mg, nilotinib 400 mg and imatinib patients respectively. Similar to what was seen with dasatinib, nilotinib demonstrated deeper and faster molecular responses when compared with imatinib [10]. In spite of the superior rates of cytogenetic and molecular responses in newly diagnosed patients treated with second generation TKIs, thus far, no overall survival benefit has been demonstrated. The 5year overall survival on the DASISION trial was 91% with dasatinib and 90% with imatinib, and this difference was not statistically significant. ENESTnd produced 4-year overall survival of 94.3% (nilotinib 300 mg BID) 96.7% (nilotinib 400 mg BID) and 93.3% (imatinib), and again, these differences did not reach statistical significance. After five years of the DASISION trial, 61% of dasatinib treated patients and 63% of nilotinib treated patient remained on their study treatment. After five years of the ENESTnd trial 60% of nilotinib 300 mg BID, 62% of nilotinib 400 mg BID and 50% of imatinib patients remained on their core treatment. Therefore, imatinib, dasatinib and nilotinib all remain viable options for treatment of newly diagnosed CML patients [4,5,9,10]. Monitoring recommendations The recommendations for monitoring patients with CML differ slightly between the ELN and the NCCN. Both committees agree that monitoring should be done at regular intervals using G-banding cytogenetics on bone marrow aspirate samples (FISH on the peripheral blood is an acceptable alternative in specific situations) as well as Q PCR to measure the BCR-ABL1 transcript levels. The PCR results must be reported using the standardized International Scale otherwise they are not able to be compared against the recommended treatment milestones [11]. The ELN recommends monitoring by cytogenetics at diagnosis, 3, 6 and 12 months after beginning TKI therapy until a patient has achieved CCyR. Once CCyR has been attained, cytogenetics should be monitored annually and FISH for BCR-ABL in the peripheral blood is an acceptable alternative to standard cytogenetics in the bone marrow. PCR monitoring is recommended every 3 months until a patient achieves MMR at which point the frequency of PCR monitoring may decrease to every 3e6 months [2]. The NCCN monitoring guidelines recommend cytogenetics at diagnosis for all patients, and at 3 and 6 months if reliable PCR reported on the International Scale is not available. If a patient has not achieved CCyR or MMR by 12 months, a bone marrow biopsy with cytogenetics is recommended at this time point. Once a patient has achieved CCyR, cytogenetics are no longer needed per the NCCN unless the patient experiences a 1-log increase in BCR-ABL transcript levels by PCR in the absence of MMR. QPCR for BCR-ABL is recommended at diagnosis and should continue every 3 months until 2 years after the patients has achieved CCyR. At that point the frequency may decrease to every 3e6 months. If a 1log increase in BCR-ABL transcripts is noted on routine monitoring, yet the patient maintains MMR, the PCR should be rechecked in 1e3 months [1]. PCR results may vary slightly over time due in part to the technical methods used in testing; therefore minor fluctuations in BCR-ABL transcript levels should not reflexively trigger repeat testing nor be the reason for changing therapy. However, significant increases of 1-log should be followed up closely [1,2]. 3-month assessment The first response assessment that may alter the course of treatment for a patient takes placed after 3 months on TKI therapy. The optimal response in all patients according to both the ELN and the NCCN is a PCR value of <10% IS at this 3 month mark. If PCR reported on the International Scale is not available or not reliable, a bone marrow biopsy with cytogenetics is indicated. The optimal response is a partial cytogenetic response (PCyR) defined as <35% Philadelphia Chromosome positive metaphases. If these
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milestones have been met, both guideline committees recommend continuation of the current therapy with repeat assessment at 6 months [1,2]. Per the ELN, treatment failure at 3 months is defined as a lack of complete hematologic response (CHR), >95% Philadelphia chromosome positive metaphases or the development of new kinase domain mutations. Therefore, if a patient fails to obtain an optimal response of BCR-ABL <10% but does not meet the specific criteria for failure, they will continue their current treatment. In this situation they fall into the warning category in which more frequent monitoring is recommended [2]. Per the NCCN, BCR-ABL transcripts >10% at 3 months warrants a change in treatment in any patient being treated with imatinib. However, if they are receiving treatment with nilotinib or dasatinib as first line therapy, the decision regarding whether or not a treatment change is indicated is left to the discretion of the treating physician. Regardless of first line therapy, anyone with BCR-ABL >10% at this time point should have a kinase domain mutation analysis (KDMA), and issues such as compliance with daily therapy and drugedrug interactions need to be addressed [1]. The prognostic significance of the 3 month molecular response is well established. Marin and colleagues reported results from a retrospective analysis of 282 CP-CML patients who received imatinib as first line therapy which indicated that those with BCR-ABL <9.84% at 3 months had significantly higher 8-year OS (93.3% vs. 56.9%), PFS (92.8% vs. 57%) and EFS (65% vs. 6.9%) compared to those with BCR-ABL >9.84% [12]. Hanfstein et al. analyzed 1303 CP-CML patients being treated with first-line imatinib from the CML IV study. In this study patients who failed to achieve a PCyR (approximately equivalent to BCR-ABL <10% IS) at 3 months had a 95% 5-year OS compared to 87% in patients with PCyR (p < 0.0001). Additionally the 5-year PFS in those with PCyR at 3 months was 92% vs. 87% in patients without PCyR at the same time period (p ¼ 0.037) [13]. Data published by Branford and colleagues further supports this, while showing the 4-year OS was 97% for patients with <10% BCR-ABL at the three month evaluation, versus 87% for those with >10%. Moreover, their data indicate that 88% of patients with <10% BCR-ABL at three months achieved MMR while only 41% of those with BCR-ABL >10% met this milestone. Interestingly, they found that of the patients who failed to meet this threemonth benchmark, the ones who ultimately had worse outcomes, were those in which the halvingtime of the BCR-ABL was >76 days. This suggests that the kinetics of the decline in BCR-ABL more so than the transcript level itself has prognostic significance [14]. Landmark analyses from the DASISION and ENESTnd trials both demonstrated that early molecular response has prognostic significance irrespective of first line therapy [15e17]. Despite consistent data suggesting inferior outcomes in patients who have BCR-ABL >10% at 3 months, neither the NCCN nor the ELN definitively recommend changing treatment at this time point. The one exception to this is the NCCN recommendation to change treatment if the first line TKI is imatinib [1,2]. This is due to the lack of data suggesting that outcomes are improved for patients who switch treatment at this time point. Furthermore, all of the data showing the prognostic impact of the 3-month assessment is retrospective, and was not part of a pre-planned analysis [12,13,15e17]. 6-month assessment By 6 months on therapy, the expectation of the NCCN is a BCR-ABL transcript level of <10% IS using QPCR on the peripheral blood just as it is at the 3-month evaluation. Irrespective of first line TKI, if a patient's BCR-ABL is >10% after 6 months, the guidelines recommend changing treatment. A KDMA as well as an assessment of patient compliance and drugedrug interactions should also take place. This is an appropriate time to consider a transplant evaluation in eligible patients as well. On the other hand, if the results of the PCR are <10%, patients are considered to be meeting the desired milestones, and should continue their current treatment [1]. The ELN has stricter guidelines at this time point, with an optimal response being defined as BCRABL transcripts <1% IS. Failure is defined as a value > 10% and anything between 1 and 10% is considered a warning [2]. Data published by Hanfstein et al. demonstrated a statistically significant improvement in 5-year overall survival in imatinib treated patients with <1% BCR-ABL transcripts at 6 months compared with those who remained >1% (97% vs. 87%, p < 0.001) [13]. A number of trials have been conducted looking at the impact of switching therapy or escalating doses of current therapy in patients with suboptimal responses to imatinib or nilotinib, and the data suggest there is a subset of patients
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who are able to achieve deeper levels of response after intensifying treatment [18,19]. For these reasons, the NCCN and the ELN recommend treatment changes for patients with >10% BCR-ABL transcripts at 6 months. 12-month assessment All patients with CP-CML should be evaluated every 3 months. At the 12 month evaluation, the NCCN considers a CCyR to be an adequate response to treatment. Therefore, in patients without a documented CCyR or MMR a bone marrow aspirate and biopsy with cytogenetics should be done to determine the cytogenetic response. It is the opinion of the guideline committee that FISH has not been adequately studied in CML and therefore should not be used as a surrogate for a bone marrow biopsy with cytogenetics. The absence of MMR in the setting of CCyR should not be considered treatment failure according to the NCCN [1]. This recommendation is based on data suggesting that early cytogenetic response is a significant prognostic factor in patients with CML, irrespective of their TKI. A study published by Jabbour and colleagues demonstrated significantly better EFS and OS in patients who achieved CCyR at 12 months (98% and 99%) compared with those who did not have CCyR at the same time point (67% and 94%) [20]. The ELN considers MMR to be an optimal response after 12 months on TKIs. Those with BCR-ABL transcripts between 0.1% and 1% are in the warning category and anything >1% or the absence of CCyR is considered treatment failure [2]. Although the definition of treatment failure is the same according to the NCCN and the ELN, the ELN considers a deeper level of molecular response to be optimal. The 5-year follow up from the IRIS trial found that no patients who had achieved MMR at 12 months progressed to accelerated or blast phase CML. Those with MMR at 12 months had a 24 month PFS of 100% compared with 95% in patients with CCyR but no MMR at 12 months [8]. Others have suggested that the absence of a 3-log reduction or MMR at any point after achieving a CCyR correlates with a significantly shorter PFS [21]. However, Hehlman et al. published data suggesting that although 3-year PFS and OS are better in patients with MMR at 12 months compared to those without MMR, further stratification of the subjects found no difference in PFS or OS in patients with MMR at 12 months compared with the group of patients whose transcripts were 0.1%e1%. The inferior outcomes were seen in those with BCR-ABL >1% at 12 months [22]. Additional studies have failed to show an improvement in PFS or OS in patients achieving MMR at 12 or 18 months compared with those patients achieving CCyR at 12 months [23,24]. Taken together these data suggest that prognostic significance is clear with CCyR at 12 months, however there is still debate surrounding the prognostic significance of MMR at the same time point. Advanced phase CML In the current era of TKI therapy for CML, progression to accelerated or blast phase CML occurs in <10% of patients who have been diagnosed in chronic phase (CP) [8e10]. In those patients who do progress to an advanced phase of CML, the recommended management differs from that of CP-CML. In AP-CML, the NCCN strongly encourages patients to be treated at a specialized center. All patients should have a KDMA and the choice of TKI should be dependent on the results of the KDMA as well as the patient's treatment history. An evaluation and donor search for an allogeneic stem cell transplant is appropriate in patients with AP-CML, however depending on the response to treatment, transplant may or may not be necessary [1]. According to the ELN, the management of AP-CML differs depending on whether a patient was diagnosed in AP or if they progressed from prior CP-CML. In those patients diagnosed in AP, the ELN recommends treatment with imatinib or dasatinib as first line therapy. They encourage a donor search for possible allogeneic stem cell transplant, but similar to the NCCN, transplant is not recommended in all patients. On the other hand, if a patient has progressed to AP-CML from prior CP, any TKI is recommended based on results of a KDMA as well as the patient's treatment history. In this setting, the ELN recommends allogeneic stem cell transplant in eligible patients with suitable donors [2]. Outcomes for patients with BP-CML have historically been very poor with the only curative option coming from an allogeneic stem cell transplant [25e27]. For this reason, the NCCN strongly
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recommends treatment at a specialized center. All patients should have a KDMA at the time of BP-CML diagnosis as this will help guide future treatment decisions. BP-CML may be lymphoid or myeloid and this distinction is an essential component of treatment decision making. Per the NCCN, lymphoid BP should be treated with either a TKI alone or an acute lymphoblastic leukemia-type induction regimen in combination with a TKI. Regardless of whether treatment is with a TKI or TKI plus induction, eligible patients must undergo an allogeneic stem cell transplant. Similarly, for those with myeloid BP, the recommended treatment includes either a single agent TKI or an acute myeloid leukemia-type induction regimen in combination with a TKI. Again, in all eligible patients, allogeneic stem cell transplant is considered the definitive treatment in these patients. The risk of post-transplant relapse is high for patients who have been transplanted for AP or BP-CML. For this reason, the NCCN recommends that post-transplant TKIs should be considered for at least one year in all patients who achieve a remission [1]. There is data to support the use of imatinib in this setting, however in patients who have already failed imatinib, another TKI should be used [1,28]. As with AP-CML, the ELN recommendations for management of BP-CML distinguish between those diagnosed in BP vs. those diagnosed in CP who have later progressed to BP-CML. Treatment with imatinib or dasatinib is recommended for patients diagnosed in BP, however any TKI is appropriate for those whose disease progressed to BP-CML. As with AP-CML, the choice of TKI should be based on the results of a KDMA as well as the patient's treatment history. In both scenarios of BP-CML, the ELN recommends allogeneic stem cell transplant for all eligible patients [2]. The primary goal of treatment prior to transplant is to return to CP-CML as this leads to the best potential outcomes after transplant [27]. Summary The evolution of effective therapeutic options in CML over the past 15 years has been dramatic, and with improved treatments come new recommendations for proper patient management. The NCCN and ELN have both published guidelines for treating patients with CP-, AP- and BP-CML. The recommended milestones at each time point in a patient's therapy are based on published data suggesting improvement in PFS or OS in patients meeting those milestones. There are minor differences in the recommendations set forth by the two committees, however the proposed definitions of treatment failure are very similar [1,2]. The projected outcomes for the vast majority of patients diagnosed with CP-CML are promising, with very few patients progressing to AP- or BP-CML. Available data suggest that patients who progress tend to do so early in their treatment course, making stringent monitoring all the more essential in the critical early months to years on TKIs [9,10,29]. Recognizing patients who are failing treatment, testing for mutations that may be responsible for resistance, and discussing issues such as potential drug interactions and compliance with therapy are necessary components for achieving optimal outcomes in patients with CML. Both sets of guidelines provide clear recommendations for when these additional tests and interventions are indicated. This is becoming all the more important now that imatinib has become generic and its use as a first line TKI is likely to increase in the coming years. Although many of these patients will respond well, this will increase the number of patients who fail to meet the early milestones, and therefore require a change in their treatment. With adherence to treatment guidelines, and adequate TKI side effect management, we can continue to see the excellent long-term survival we have come to expect in patients with CP-CML. Conflict of Interest KS is on the speakers bureau for Novartis, Pfizer and Araid and is a consultant for Novartis and Ariad. JPI is on the speakers bureau for Bristol Myer Squibb and Pfizer and is a consultant for Novartis, Bristol Myer Squibb, Pfizer and Ariad.
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