Accepted Manuscript Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors Pradnya Chopade, Luke P. Akard PII: S2152-2650(18)30343-4 DOI: 10.1016/j.clml.2018.06.029 Reference: CLML 1156 To appear in: Clinical Lymphoma, Myeloma and Leukemia Received Date: 5 April 2018 Revised Date: 20 June 2018 Accepted Date: 28 June 2018 Please cite this article as: Chopade P, Akard LP, Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors, Clinical Lymphoma, Myeloma and Leukemia (2018), doi: 10.1016/j.clml.2018.06.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 2 Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Pradnya Chopade 1 and Luke P. Akard 2 1,2 Indiana Blood and Marrow Transplantation, Franciscan St. Francis Hospital and Health Centers, Indianapolis, IN, USA; 1 Email: pradnya.chopade@gmail.com; 2 Email: lakard@ibmtindy.com Corresponding author: Luke P. Akard, MD Indiana Blood and Marrow Transplantation Franciscan St. Francis Hospital and Health Centers Suite 207 Indianapolis, IN 46237 Telephone: (317) 528-5500 Fax: (317) 528-6316 Target journal: Clinical Lymphoma, Myeloma & Leukemia Short title: Improving Outcomes in Chronic Myeloid Leukemia 1
22 23 Conflict of interest: PC: has nothing to disclose. LPA: Bristol-Myers Squibb: personal fees during the conduct of the study; Novartis: personal fees and non-financial support during the 24 25 26 conduct of the study; Takeda: personal fees during the conduct of the study; Celgene: personal fees outside the submitted work; Gilead: personal fees outside the submitted work. 2
27 28 Abstract Most patients with chronic myeloid leukemia (CML) receiving treatment with BCR-ABL1 tyrosine 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 kinase inhibitors (TKIs) achieve favorable responses; moreover, TKI therapy enables patients to achieve long-term survival, with survival rates similar to those of individuals without CML. This enhanced survival has resulted from the availability of multiple BCR-ABL1 TKIs with efficacy not only in frontline treatment, but importantly, also in second- and third-line treatment. Here, we review the changes in long-term outcomes in the era of TKI therapy and how these changes have impacted treatment practices. We discuss the development of imatinib, the first BCR-ABL1 TKI, followed by newer TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib. We consider the key studies that led to their development as frontline or later-line therapies, their safety profiles, and their impact on improving patient outcomes. Due to these improved outcomes, the definition of an optimal response has become more stringent, and treatment monitoring strategies have changed. Second-line patient populations have evolved from those with resistance to or intolerance of imatinib, to those with moderate responses to or low-grade adverse events with imatinib. Although all TKIs are associated with high survival rates, newer TKIs are associated with lower disease progression rates and, importantly, deeper treatment responses and, potentially, a greater chance of future treatment-free remission. Finally, we consider the unmet needs of patients with CML, including the challenges remaining for those who do not have optimal responses with TKIs as well as new therapies and strategies to identify them at diagnosis. Keywords: BCR-ABL1, clinical trial, molecular monitoring, Philadelphia chromosome, treatment-free remission 50 3
51 52 Abbreviations 2G = second generation 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 3G = third generation AE = adverse event AP/BC = accelerated phase/blast crisis CCyR = complete cytogenetic response CHR = complete hematologic response CML = chronic myeloid leukemia CML-CP = chronic myeloid leukemia in chronic phase CVE = cardiovascular event ELN = European LeukemiaNet EMR = early molecular response HSCT = hematopoietic stem cell transplant IS = International Scale MCyR = major cytogenetic response MMR = major molecular response MR 4 = BCR-ABL1 IS 0.01% MR 4.5 = BCR-ABL1 IS 0.0032% NCCN = National Comprehensive Cancer Network Ph = Philadelphia chromosome TFR = treatment-free remission TKI = tyrosine kinase inhibitor UMRD = undetectable minimal residual disease 74 4
75 76 Introduction The identification of the Philadelphia chromosome (Ph) in chronic myeloid leukemia (CML) in 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 1960 led to the understanding that this disease arises from a translocation between chromosomes 9 and 22. 1,2 This translocation results in creation of the oncogenic BCR-ABL1 fusion gene, which codes for the constitutively active BCR-ABL1 tyrosine kinase. 3 Shortly after the discovery of the BCR-ABL1 tyrosine kinase, Brian Druker led a group that identified imatinib, a selective inhibitor of the ABL kinase, which effectively inhibited the growth of BCR-ABL1 positive cells. 4 This quickly led to a clinical trial in patients with CML who had unfavorable responses to interferon, the preferred treatment at the time. 5 In this trial, 60% of patients with CML for whom prior interferon therapy had failed were able to achieve a major cytogenetic response (MCyR; 35% Ph-positive [Ph+] metaphases) with imatinib. Based on this result, a large, global, phase 3 trial was conducted that compared imatinib vs interferon plus cytarabine in patients with newly diagnosed CML in chronic phase (CML-CP). 6 The results of this study (the International Randomized Study of Interferon and STI571 [IRIS]) further demonstrated the benefits of imatinib over interferon: at 18 months of treatment, most patients receiving imatinib had achieved a complete cytogenetic response (CCyR; 0% Ph+ metaphases). Not only did imatinib result in better responses than interferon-based treatment, it was also much better tolerated. Shortly thereafter, imatinib became the standard of care, and it was recognized that allogeneic hematopoietic stem cell transplant (HSCT) could be reserved for cases of tyrosine kinase inhibitor (TKI) failure. 7 These imatinib trials impacted CML response assessment strategies in several ways. First, with patients achieving deeper responses than were previously typical, new criteria were needed to 98 99 100 define the responses to and outcome expectations with imatinib therapy. For example, because nearly all imatinib-treated patients achieved normalized blood counts and the majority achieved a CCyR, 6 complete hematologic responses (CHRs) and CCyRs became the norm and were no 5
101 102 longer sufficient to define an optimal response. Instead, a major molecular response (MMR; BCR-ABL1 0.1% on the International Scale [BCR-ABL1 IS ]), indicating a 3-log decrease in 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 BCR-ABL1 transcripts relative to the standard baseline pretreatment level, became a key threshold indicating successful CML treatment. 7,8 Second, it was found that these strong treatment responses could be indicative of good future outcomes. For example, patients with an MMR had little likelihood of disease progression compared with patients lacking an MMR. 9 However, not all patients receiving imatinib had optimal responses; therefore, primary failure, acquired resistance, and loss of response had to be defined in the context of imatinib therapy. Criteria for imatinib dose escalation due to insufficient response were used in the phase 2 trial examining imatinib in patients with interferon failure 5 ; loss of response to imatinib was also defined early in the TKI era. 10 For patients who experienced imatinib failure, increasing the dosage or switching to interferon plus cytarabine provided little help. 6,11 Fortunately, secondand third-generation TKIs (2G-TKIs and 3G-TKIs, respectively) were developed and proved to be effective in patients with CML-CP who had developed resistance to or failure of imatinib therapy. 11-18 Further evidence of the efficacy of TKI treatment comes from population studies. Per the National Cancer Institute s Surveillance, Epidemiology, and End Results program, the annual age-adjusted mortality rate in patients with CML in the United States fell from 0.9 per 100,000 in 1998 (the year the initial trials of imatinib commenced) to 0.3 per 100,000 in 2013. 19 Another study showed that patients who achieved a CCyR after 2 years on imatinib had a survival rate similar to that of individuals without CML and a low likelihood of dying from CML during the initial decade of treatment. 20 Similarly, a Swedish registry study showed a dramatic increase in 124 125 life expectancy in patients with CML and noted that patients now have a life expectancy nearing that of the general population. 21 126 6
127 128 Guidelines for monitoring CML and response milestones to gauge treatment success have been developed by both the National Comprehensive Cancer Network (NCCN) and European 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 LeukemiaNet (ELN). In the earliest guidelines, treatment targets focused on hematologic and bone marrow cytogenetic responses. 7,22 Over time, these guidelines evolved to focus on molecular response levels, and the response thresholds delineating patients who are responding well to treatment vs those who should be switched to a new treatment have become increasingly stringent. 23,24 This article reviews the improvements in treatment responses and outcomes in patients with CML since the introduction of imatinib and, subsequently, the 2G- and 3G-TKIs nilotinib, 25 dasatinib, 26 bosutinib, 27 and ponatinib. 28 The impact of these improvements on treatment goals and the definition of frontline-treatment failure, the change in the characteristics of patients receiving second-line treatment, ongoing treatment challenges, and the emergence of treatment-free remission (TFR) are discussed as well. Imatinib and the beginning of the TKI era Results from the IRIS trial, first published in 2003, dramatically changed the expectations for CML treatment outcomes. 6 Estimated rates of MCyR at 18 months were 87.1% in the imatinib arm vs 34.7% in the interferon plus cytarabine arm (P <.001). Estimated rates of CCyR at 18 months were 76.2% vs 14.5%, respectively (P <.001). Further, estimated rates of freedom from progression to accelerated phase or blast crisis (AP/BC) at 18 months were 96.7% vs 91.5%, respectively (P <.001). In addition to being more effective, imatinib was better tolerated than interferon plus cytarabine, with fewer grade 3/4 adverse events (AEs) and fewer patients switching treatment due to AEs or intolerance. The most frequent AEs reported with imatinib (with a median follow-up of 19 months) were superficial edema (55.5%), nausea (43.7%), 150 151 muscle cramps (38.3%), musculoskeletal pain (36.5%), rash (33.9%), fatigue (34.5%), diarrhea (32.8%), and headache (31.2%). 152 7
153 154 Five-, 29 6-, 30 and 10-year 31 outcomes from the IRIS trial have been reported, confirming the durability of response in most patients and helping to define the safety and long-term toxicities 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 of imatinib. Long-term results, with a median follow-up of 10.9 years, showed that 48.3% of patients randomized to receive imatinib completed the study treatment; moreover, the estimated overall survival rate at 10 years was 83.3% with imatinib, and the CCyR rate was 82.8%. 31 Notably, most instances of disease progression in patients on imatinib occurred during the first 4 years of treatment. 31 Most patients in the interferon plus cytarabine arm either crossed over to imatinib (65.6%) on study or discontinued treatment (33.1%). 31 Because of this, a long-term comparison between imatinib and interferon plus cytarabine was not possible. However, a retrospective analysis comparing the outcomes of patients receiving imatinib in the IRIS study with the outcomes of patients receiving interferon plus cytarabine in the CML91 study showed that responses to imatinib therapy translated into improvements in survival relative to interferon plus cytarabine therapy. 32 Among all patients randomly assigned to receive imatinib, with a median follow-up of 10.9 years, the reasons for discontinuing treatment in > 1% of patients were unsatisfactory therapeutic effect (15.9%), withdrawal of consent (10.3%), AEs (6.9%), no longer requiring study drug owing to bone marrow transplant (3.8%), death (3.4%), protocol violations (3.1%), loss to follow-up (2.7%), and administrative problems (2.2%). 31 Only 2.5% crossed over to the interferon plus cytarabine arm. Eighty-nine participants assigned to imatinib (16.1%) died during the trial, 50 (9.0%) due to CML, 11 (2%) from a secondary malignancy, 7 (1.3%) from a cardiac disorder or cardiovascular disease, and 5 (0.9%) from infection. Serious AEs related to the study drug occurred in 51 of 551 patients on imatinib (9.3%) and were most frequent during the 176 177 first year of treatment. Cardiac serious AEs of any cause were reported in 39 patients (7.1%), while serious AEs of a second neoplasm, benign or malignant, were reported in 62 patients 8
178 179 (11.3%). The relationship between imatinib and both cardiovascular and second-neoplasm long- term AEs remains to be fully assessed. 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 Several other studies have further assessed and confirmed the safety and efficacy of imatinib in the treatment of CML. The Hammersmith group evaluated the results of imatinib treatment in a long-term longitudinal trial, and reported durable responses in most imatinib-treated patients. 33 The German CML-study IV trial included 1379 imatinib single-agent-treated patients; at a median follow-up of 7.1 years, 64% of patients remained on the trial receiving imatinib, with 10- year rates of progression-free survival, overall survival, and MMR of 82%, 84%, and 89%, respectively. 34 Twenty-two percent of patients had grade 3/4 adverse drug reactions, the majority of which occurred during the first 3 years of treatment. Molecular monitoring, which had previously been used to monitor for minimal residual disease in patients who received allogeneic HSCT, 22 became standard during TKI treatment as a result of the IRIS trial. While all patients in this trial had their hematologic and cytogenetic responses monitored, a subset also had their molecular responses carefully monitored throughout treatment within exploratory substudies. It was observed that many patients with a CCyR went on to achieve deeper levels of response that could be quantified at the molecular level in peripheral blood using real-time quantitative polymerase chain reaction to measure BCR-ABL1 transcript levels. These molecular responses were demonstrated to be predictive of long-term treatment outcomes. 9,35,36 The molecular testing methodology varied between the laboratories performing this test and, therefore, a need arose for standardized reporting so that results from different testing sites could be compared. This led to international cooperation for development 201 202 of the IS, a standardization tool for quantifying and interpreting molecular responses that was proposed concurrently with the IRIS study. 37 All standard molecular response level definitions, 9
203 204 such as MMR, MR 4 (BCR-ABL1 IS 0.01%), and MR 4.5 (BCR-ABL1 IS 0.0032%), are now based on the IS. 38 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 Shortly after the initial results from IRIS were published, guidelines for monitoring and treating CML were proposed by both the NCCN (2005) 39 and ELN (2006). 7 The NCCN Guidelines recommended imatinib, allogeneic HSCT, or participation in a clinical trial as frontline treatment. 39 The ELN recommended frontline imatinib treatment and defined failure as no hematologic response at 3 months, incomplete hematologic response or no cytogenetic response at 6 months, Ph+ > 35% at 12 months, or Ph+ > 0% at 18 months. 7 The options for second-line treatment included imatinib dose escalation, allogeneic HSCT, or investigational treatment. Early data on second-line therapy with 2G-TKIs In 2005, phase 2 trials began testing the 2G-TKIs nilotinib and dasatinib in the second-line treatment of patients with CML who were resistant to or intolerant of frontline imatinib. Each of these trials had slightly different enrollment criteria (Table 1). 15,16 In the pivotal trial of secondline nilotinib (referred to as Study 2101), resistance to imatinib was defined as lack of CHR by 3 months, no cytogenetic response by 6 months, no MCyR by 12 months, or loss of hematologic or cytogenetic response at any time. 15 Additionally, patients must have received imatinib 600 mg once daily for 3 months. In the second-line dasatinib trial (CA180-034), resistance to imatinib was defined as no decrease in white blood cell count after 4 weeks, no CHR after 3 months, no MCyR after 6 months, no CCyR after 12 months, loss of MCyR or loss of confirmed CHR, loss of molecular response with 10% Ph+ metaphases, or identification of a new BCR- 226 ABL1 mutation. 16 227 10
228 229 These studies showed that the 2G-TKIs have excellent efficacy and tolerability. With a minimum follow-up of 2 years in the nilotinib 2101 study, nilotinib 400 mg twice daily demonstrated a 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 cumulative MCyR rate of 59% (patients with imatinib resistance, 56%; patients with imatinib intolerance, 66%) and a CCyR rate of 44% (41% and 51%, respectively). 40 In the 4-year analysis, the estimated progression-free survival rate was 57% (95% CI, 51%-64%) and the most common nilotinib-related nonhematologic AEs included rash (31%), pruritus (26%), nausea (25%), fatigue (21%), and headache (18%), all of which were primarily grade 1/2. 41 After a minimum follow-up of 2 years in the dasatinib CA180-034 study, the cumulative MCyR rate with dasatinib 100 mg once daily was 63% (patients with imatinib resistance or suboptimal response, 59%; patients with imatinib intolerance, 77%), while the cumulative CCyR rate was 50% (44% and 67%, respectively). 42 The most common dasatinib-related nonhematologic AEs included headache (33%), diarrhea (25%), fatigue (24%), dyspnea (19%), and musculoskeletal pain (19%). In the final analysis, the estimated progression-free survival rate at 7 years was 39% (95% CI, 29%-49%) in patients with imatinib resistance and 51% (95% CI, 32%-67%) in those with imatinib intolerance. 43 These pivotal studies led to the approval of nilotinib in 2007 and dasatinib in 2006 in the United States for use as second-line treatments in patients with frontline imatinib resistance or intolerance. 44,45 The success of these 2G-TKIs was followed by bosutinib, a 2G-TKI that inhibits SRC and ABL1 tyrosine kinases. 11 Long-term data are available from a phase I/II trial (Study 200) of 286 patients (196 imatinib resistant; 90 imatinib intolerant) treated with bosutinib 500 mg daily. 46 After a median follow-up of 44 months, the cumulative MCyR rate was 59% and the 251 252 253 cumulative CCyR rate was 49%. 46 The Kaplan-Meier-estimated 2-year overall survival rate was 88% in patients with imatinib resistance and 98% in patients with imatinib intolerance. 46 The most common toxicity, with a median follow-up of 44 months, was diarrhea (86%). 46 11
254 255 Expansion of the TKI era 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 The high response rates to second-line nilotinib and dasatinib in patients with frontline imatinib resistance raised the possibility that these 2G-TKIs might have improved efficacy compared with imatinib in frontline treatment. The usefulness of nilotinib as frontline therapy was first established in the pivotal Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) trial, which compared 2 doses of nilotinib (300 mg twice daily and 400 mg twice daily) vs imatinib 400 mg once daily in patients with newly diagnosed CML- CP. 47 In the 1-year analysis of ENESTnd, patients receiving nilotinib achieved higher rates of CCyR and MMR vs those receiving imatinib. Cumulative CCyR rates by 12 months were 80%, 78%, and 65% in the nilotinib 300-mg twice-daily, nilotinib 400-mg twice-daily, and imatinib arms, respectively (P <.001 for each nilotinib arm vs the imatinib arm). MMR rates at 12 months, the primary endpoint, were 44%, 43%, and 22%, respectively (P <.001 for each nilotinib arm vs the imatinib arm). With longer follow-up, nilotinib continued to result in improved responses, including higher rates of MMR (77% in each nilotinib arm vs 60% in the imatinib arm by 5 years; P <.0001) and MR 4.5 (54% in the nilotinib 300-mg twice-daily arm, 52% in the nilotinib 400-mg twice-daily arm, and 31% in the imatinib arm by 5 years; P <.0001). 48 Compared with imatinib, nilotinib also resulted in higher rates of early molecular response (EMR, BCR-ABL1 IS 10% at 3 months; 91%, 89%, and 67% of evaluable patients in the nilotinib 300-mg twice-daily, nilotinib 400-mg twice-daily, and imatinib arms, respectively), freedom from progression to AP/BC (estimated rates at 5 years: 96.3% [P =.0403 vs imatinib], 97.8% [P =.0028 vs imatinib], and 92.1%, respectively), and freedom from CML-related death 277 278 279 (estimated rates at 5 years: 97.7% [P =.0292 vs imatinib], 98.5% [P =.0057 vs imatinib], and 93.8%, respectively). 48,49 Notably, the improvements in early and deep molecular response rates with nilotinib over imatinib were observed across all Sokal risk groups, and the reduced risk of 12
280 281 progression to AP/BC with nilotinib compared with imatinib was noted in both the intermediate- and high-risk groups (few patients with low Sokal risk scores progressed in any arm). 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 In parallel with ENESTnd, the Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients (DASISION) trial compared the safety and efficacy of frontline dasatinib 100 mg once daily vs imatinib 400 mg once daily in patients with newly diagnosed CML-CP. 50 Patients receiving dasatinib achieved higher rates of CCyR and MMR by 12 months vs patients receiving imatinib (CCyR: 83% vs 72% [P =.001]; MMR: 46% vs 28% [P <.0001], respectively). 50 Higher rates of EMR were also reported in patients on dasatinib compared with imatinib (84% vs 64%, respectively; P <.0001). 51 Throughout 5 years of follow-up, molecular response rates remained higher among patients receiving dasatinib vs those receiving imatinib (MMR: 76% vs 64%, respectively [P =.0022]; MR 4.5 : 42% vs 33%, respectively [P =.0251]). 52 Within each Hasford risk group, response rates tended to be higher with dasatinib vs imatinib. There were 9 vs 17 CML-related deaths among patients in the dasatinib arm vs imatinib arm, respectively. However, the estimated 5-year overall survival rate was not statistically significantly different between the dasatinib arm vs imatinib arm (91% vs 90%; P =.9800); the estimated 5-year progression-free survival rate was 85% in the dasatinib arm and 86% in the imatinib arm (P =.7934). Bosutinib, which is also approved for use as frontline therapy, 27 and the 3G-TKI ponatinib, which is not currently indicated for use as frontline therapy, 28 have both been evaluated in randomized studies vs imatinib in patients with newly diagnosed CML-CP. 53-55 The Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) study compared outcomes with bosutinib 500 mg once daily vs imatinib 400 mg once daily. 53 In the primary endpoint analysis, 303 304 305 CCyR rates at 12 months were similar with bosutinib or imatinib (70% vs 68%, respectively; P =.601). However, bosutinib did result in higher rates of MMR at 12 months vs imatinib (41% vs 27%, respectively; P <.001). It should be noted that the BELA trial appeared to have a high 13
306 307 dropout rate in the bosutinib arm, largely due to AEs, which could have impacted the results. 53,56 Subsequently, another study (the Bosutinib Trial in First Line Chronic Myelogenous Leukemia 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 Treatment [BFORE]) was designed to evaluate the safety and efficacy of a lower bosutinib dose (400 mg daily) as frontline therapy. 54 Unlike the BELA trial, preliminary results from the BFORE trial showed that 12-month CCyR and MMR rates were both superior with bosutinib 400 mg daily vs imatinib 400 mg daily (CCyR by 12 months: 77.2% vs 66.4%, respectively [P <.008]; MMR at 12 months: 47.2% vs 36.9%, respectively [P =.02]). At 18 months of follow-up, patients in the bosutinib arm vs imatinib arm had MMR rates of 56.9% vs 47.7% (P =.042) and MR 4.5 rates of 11.4% vs 7.1% (P =.1075), respectively. 57 Overall survival rates at 18 months were 99.6% vs 96.6% in the bosutinib arm vs imatinib arm, respectively; the cumulative rates of progression to AP/BC at 18 months were 2.0% and 2.9%, respectively. Following these results, bosutinib was approved for use as frontline treatment in patients with CML-CP. 27 Ponatinib is the only available TKI that has activity against BCR-ABL1 with the T315I mutation. Activity of this drug in patients who have experienced resistance to or unacceptable adverse effects with 2 TKIs has been good. 18 However, significant cardiovascular toxicity has limited its use to patients with the T315I mutation or those for whom no other TKI is expected to be effective. 58 The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was designed to compare the outcomes with ponatinib 45 mg once daily vs imatinib 400 mg once daily in patients with newly diagnosed CML-CP. 55 However, due to safety concerns that arose around the time that EPIC was initiated, the study was terminated early and the primary endpoint could not be assessed. Thus, the efficacy and safety of frontline ponatinib have not been thoroughly evaluated. However, among patients enrolled in EPIC prior to its 329 330 termination who had evaluable molecular response assessments, ponatinib appeared to result in higher rates of EMR than imatinib (94% [103/109] vs 68% [77/114], respectively; P <.0001). 331 14
332 333 The outcomes achieved (and assessed) in IRIS compared with those of these pivotal trials of newer TKIs illustrate the dramatic improvements in prognosis that have occurred in patients with 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 CML-CP in the time since IRIS was initiated (Table 2). TKI safety profiles Each TKI is associated with a distinct safety profile. 6,47,48,50,52,53,55,56,59 The safety profile of imatinib has been consistent across trials. With 5 years of follow-up in ENESTnd, the most frequent nonhematologic AEs (regardless of relationship to study treatment) reported with frontline imatinib included diarrhea (46.1%), nausea (41.1%), muscle spasms (33.9%), and vomiting (26.8%). 48 In DASISION, with 3 years of follow-up (cumulative AE rates were not reported in the 5-year analysis), the most frequent drug-related nonhematologic AEs with imatinib included myalgia (41%), superficial edema (37%), nausea (24%), diarrhea (22%), and rash (18%). 51 With 5 years of follow-up in ENESTnd, the most frequent nonhematologic AEs (regardless of relationship to study treatment) reported with frontline nilotinib at either 300 or 400 mg twice daily included rash (38.4%; 44.8%, respectively), headache (31.9%; 36.1%), nasopharyngitis (26.9%; 22.7%), fatigue (23.3%; 19.5%), and nausea (22.2%; 30.7%). 48 Nilotinib was also associated with newly occurring or worsening grade 3/4 elevations in lipase (9.0%; 10.1%), glucose (7.2%; 6.9%), alanine aminotransferase (4.3%; 9.4%), and total bilirubin (4.3%; 9.0%), and decreases in phosphate (7.9%; 10.1%). Although not among the most frequent AEs with nilotinib, cardiovascular events (CVEs) have been reported more frequently during nilotinib treatment vs imatinib treatment; in ENESTnd, 7.5%, 13.4%, and 2.1% of patients in the nilotinib 355 356 300-mg twice-daily, nilotinib 400-mg twice-daily, and imatinib arms, respectively, had a CVE by the 5-year data cutoff. 357 15
358 359 With 3 years of follow-up in DASISION, the most frequent dasatinib-related nonhematologic AEs included myalgia (23%), diarrhea (21%), pleural effusion (19%), superficial edema (13%), rash 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 (13%), and headache (13%). 51 Pulmonary hypertension has emerged as a safety concern with dasatinib and was reported in 5% of dasatinib-treated patients in DASISION by 5 years. 52 Similar to nilotinib, dasatinib has been associated with a higher rate of ischemic events vs imatinib, reported in 5% of dasatinib-treated vs 2% of imatinib-treated patients in DASISION by 5 years. With 2 years of follow-up in BELA, the most frequent treatment-emergent AEs with bosutinib included diarrhea (70%), nausea (32%), vomiting (32%), increased alanine aminotransferase (32%), thrombocytopenia (28%), and increased aspartate aminotransferase (27%). 56 Diarrhea has emerged as a key tolerability factor for bosutinib, although it was typically controllable with proper treatment. 53,56 CVEs were reported in 10% and 8% of bosutinib- and imatinib-treated patients in BELA, respectively, by the 2-year analysis. 56 In the BFORE trial, which used a lower dose of bosutinib (400 mg daily vs 500 mg daily in BELA), diarrhea and CVEs were again reported. 57,60 With 18 months of follow-up, diarrhea was reported in 72% vs 36% of patients receiving bosutinib vs imatinib. 60 Cardiovascular, peripheral vascular, and cerebrovascular events were also reported (3.4%, 1.9%, 0.4%, respectively, with bosutinib; 0.0%, 1.1%, 0.8%, respectively, with imatinib). 57 With a median follow-up of 5 months among ponatinib-treated patients in EPIC before the trial was terminated, the most frequent treatment-emergent nonhematologic AEs in the ponatinib arm included rash (38%), abdominal pain (36%), headache (32%), constipation (27%), 381 382 383 increased lipase (27%), and myalgia (26%). 55 As noted above, CVEs have emerged as a particular concern with ponatinib therapy; among patients enrolled in EPIC, 7% vs 2% of those in the ponatinib arm vs imatinib arm, respectively, had an arterial occlusive event before the 16
384 385 study was terminated, and 1 patient in the ponatinib arm had a serious venous thromboembolic event. Although limited safety data are available from this study due to the short follow-up 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 duration, the safety results with ponatinib were consistent with those from the Ponatinib Ph- Positive Acute Lymphoblastic Leukemia and CML Evaluation (PACE) trial, a pivotal study of second- or later-line ponatinib. 18,55 Evolution of CML treatment guidelines With improvements in CML treatments and patient outcomes, CML management recommendations from the NCCN and ELN have become progressively more stringent in their designation of target response levels and response levels at which patients should switch treatment. 7,8,23,24,39,61-66 The response thresholds below which a patient s TKI should be switched may depend on the patient s individual characteristics, treatment goals, and clinical situation. Thus, both the NCCN and ELN have created multiple response categories to distinguish among patients who should immediately switch to a new treatment (referred to as the treatment failure or red category by the ELN and NCCN, respectively), those who should remain on their current treatment ( optimal response or green category, respectively), and those with intermediate levels of response, for whom a treatment switch may or may not be appropriate ( warning or yellow category, respectively). 23,24 The NCCN introduced its color-coded response categories in the 2017 guidelines and has continued them in the 2018 version (Figure 1) 8,23 ; however, prior versions of the guidelines similarly included multiple response categories, each with distinct management recommendations. 39,61,62 Table 3 summarizes the evolution of the response levels at which the NCCN recommends considering a change in treatment, including TKI dose escalation or switching to an alternative therapy. 407 408 409 The recommended methods for monitoring CML have also changed over time. While the NCCN s 2005 guidelines recommended bone marrow testing as part of routine disease 17
410 411 monitoring, the 2018 guidelines recommend cytogenetic testing of marrow only at diagnosis, upon failure to reach response milestones, and at any sign of loss of response. 23,39 Following 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 the success of clinical trials of TFR in patients who have achieved sustained and deep molecular responses, the 2018 guidelines also contain recommendations for attempting TFR outside of clinical trials, including eligibility criteria and a schedule of standardized molecular monitoring. 23 Thus, the recent NCCN guidelines have been strongly influenced by the successful availability and application of standardized molecular testing and the results of clinical TFR studies. Evolution of second-line patient populations As discussed above, enrollment in the initial studies of second-line nilotinib and dasatinib was restricted to patients who were resistant to or intolerant of frontline imatinib. By comparison, more recent studies of second-line TKI therapy have focused on patients with moderate response levels to or persistent low-grade AEs with frontline TKIs (Table 1). For example, the ENEST-Complete Molecular Response (ENESTcmr) study investigated the impact of a switch to nilotinib on achievement of a deep molecular response in patients with a CCyR but detectable BCR-ABL1 after 2 years of frontline imatinib therapy. 67 The TIDEL-II study evaluated a treatment strategy in which all patients were started on frontline imatinib, and those who missed stringent time-based response targets (EMR, BCR-ABL1 IS 1% at 6 months, or MMR at 12 months) were either rapidly switched to nilotinib or initially dose escalated and subsequently switched to nilotinib if they failed the same target 3 months later (depending on the cohort to which they were assigned). 68 This strategy resulted in high response rates: at 12 months, 64% of patients achieved a confirmed MMR and 19% achieved MR 4.5. Several other ongoing studies 433 434 435 (including SUSTRENIM [NCT02602314], DASCERN [NCT01593254], and BOSTRO [NCT02445742]) are evaluating treatment switches for similar missed milestones, although results of these studies are not yet available. 69-71 18
436 437 One relatively unexplored topic is second-line treatment outcomes in patients who switched 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 from frontline 2G-TKIs due to intolerance or lack of efficacy. A study of 218 patients who received either frontline nilotinib or dasatinib reported that 40 of them stopped the initial TKI due to AEs, lack of response, or other reasons. 72 Among those initiating a second-line treatment, therapies included imatinib, nilotinib, dasatinib, dasatinib plus chemotherapy, bafetinib, ponatinib, and allogenic HSCT. Nineteen of these 40 patients (48%) achieved a CCyR, including 17 (43%) with an MMR after the switch to the second treatment. Survival, disease progression, and TFR in the TKI era Although there are notable differences between the available frontline TKIs in terms of response rates and CML progression, no difference in overall survival has been observed. 48,52 The ENESTnd trial had 1 arm, the non-approved dose of nilotinib 400 mg twice daily (approved dosage is 300 mg twice daily) that, compared with the imatinib arm, showed both improved event-free survival (96.9% vs 92.6%, respectively; P =.0188) and overall survival (96.2% vs 91.7%, respectively; P =.0266) at 5 years. 48 Although these outcomes may serve as proof of principle that more potent inhibition of BCR-ABL1 may result in improved outcomes, the relevance of these improvements is not clear, because this is not the approved dose of nilotinib and the study was not powered to statistically compare survival rates between arms. Nevertheless, with approved dosages, all frontline TKIs are associated with high rates of overall survival, 48,52,57 and patients with CML who respond to TKI treatment now have a life expectancy comparable to that of the general population. 20,21 Additionally, for patients receiving frontline TKI therapy, achievement of a CCyR is associated with improved survival. 73 In a single-institution 459 460 461 analysis of 435 patients with newly diagnosed CML-CP receiving either imatinib or 2G-TKI therapy, those with a CCyR at 12 months vs those without a CCyR at 12 months had 3-year overall survival rates of 99% vs 94%, respectively (P <.001). 73 19
462 463 Avoidance of CML progression to AP/BC remains an important goal of TKI therapy because 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 unlike for CML-CP, survival rates following progression to AP/BC are poor; in an analysis based on data from ENESTnd and IRIS, the median duration of overall survival following progression to AP/BC was 10.5 months. 74 An analysis from the IRIS study showed that patients receiving frontline imatinib who achieved an MMR at 12 or 18 months were less likely to progress to AP/BC than those without an MMR (estimated rates of freedom from progression to AP/BC at 7 years according to MMR vs no MMR at 12 months: 99% vs 89.9%, respectively [P =.0004]; according to MMR vs no MMR at 18 months: 99.1% vs 90.1%, respectively [P <.001]). 36 Importantly, development of newer TKIs since the introduction of imatinib has resulted in reduced rates of CML progression. In ENESTnd, for example, with a minimum follow-up of 5 years, 3.5%, 2.1%, and 7.4% of patients in the nilotinib 300-mg twice-daily, nilotinib 400-mg twice-daily, and imatinib arms, respectively, had progressed to AP/BC. 48 In DASISION, 4.6% of patients receiving dasatinib and 7.3% of those receiving imatinib progressed to AP/BC by the 5- year analysis. 52 Similarly, in BFORE, the cumulative rates of progression to AP/BC at 18 months in patients receiving bosutinib and imatinib were 2.0% and 2.9%, respectively. 57 Since newer treatments are producing faster and deeper molecular responses, there is an increasing focus on the clinical relevance of these responses. In some studies, deep molecular responses have been shown to result in improved clinical outcomes, including lower risks of disease progression and death. 75,76 However, the most clearly established benefit of achieving a deep molecular response is the potential to become eligible to stop treatment and attempt TFR. 77 Recommended criteria for attempting TFR, including prior TKI duration and prior 485 486 487 molecular response depth and duration, have been published in the NCCN guidelines, the European Society for Medical Oncology (EMSO) CML clinical practice guidelines, the French Chronic Myeloid Leukemia Study Group TFR guidelines, as well as in multiple publications from 20
488 489 international CML experts. 23,78-81 The NCCN guidelines recommend 3 years of TKI therapy and stable molecular response (MR 4 ) for 2 years. 23 The ESMO guidelines recommend > 5 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 years of TKI therapy, achievement of MR 4.5, and > 2 years of deep molecular response (MR 4 or MR 4.5 ). 78 The French guidelines recommend 5 years of TKI therapy and 2 years of MR 4.5. 79 Additionally, a review by Hughes and Ross recommends > 8 years of TKI therapy and MR 4.5 for > 2 years while a review by Saussele et al makes no recommendation regarding minimum TKI duration but recommends MR 4 for a duration of 2 years. 80,81 Regular molecular monitoring of patients in TFR is critical to ensure rapid detection of rising BCR-ABL1 transcript levels; the TFR guidelines and expert recommendations described above therefore include recommended molecular monitoring schedules, typically with a high monitoring frequency for the first 6-12 months after stopping TKI therapy and less frequently thereafter. 23,78-81 The NCCN guidelines recommend monthly monitoring for the first year of TFR, every 6 weeks for the second year, and every 12 weeks afterwards. 23 The ESMO guidelines recommend monitoring every month for the first 6 months, every 6 weeks for the next 6 months, and every 3 months thereafter. 78 The French guidelines recommend monitoring monthly for the first 6 months, every 2 months for the next 6 months, quarterly for the next 12 months, and every 3 to 6 months afterwards. 79 Hughes and Ross recommend monitoring closely during the first 6 months and less frequently, such as every 2-3 months, thereafter. 80 Saussele et al recommend monitoring every 4 weeks for the first 6 months, every 6 weeks for the next 6 months, and every 3 months afterwards. 81 Clinical trials of TFR have reported that 40% to 70% of patients who ceased imatinib, nilotinib, 511 512 513 or dasatinib treatment maintained successful TFR (Table 4). 82-101 In the early TFR clinical trial Stop Imatinib (STIM1), patients with 3 years of imatinib therapy and 2 years of undetectable minimal residual disease (UMRD) attempted to stop treatment without losing their deep 21
514 515 response; following treatment stop, if 2 consecutive assessments showed loss of UMRD (with a 1-log increase in BCR-ABL1 in the second assessment) or if a single assessment showed loss 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 of MMR, treatment was reinitiated. The 60-month Kaplan-Meier-estimated TFR rate in the STIM1 cohort was 38%. 83 Subsequently, the According to STIM (A-STIM) study also assessed TFR in patients with 3 years of frontline imatinib therapy and 2 years of UMRD; however, in this study, therapy was resumed only after loss of MMR (not confirmed loss of UMRD). 85 The 36-month Kaplan-Meier-estimated TFR rate in A-STIM was 61%. In the European Stop Kinase Inhibitors trial, patients with 3 years of TKI therapy (imatinib, nilotinib, or dasatinib) and MR 4 for 1 year were eligible to attempt TFR; with loss of MMR as the criterion for reinitiating treatment, the 24-month Kaplan-Meier-estimated rate of molecular relapse- and treatment-free survival was 49%. 97 TFR in patients taking the second-generation TKIs nilotinib or dasatinib (frontline or subsequent line) was examined in the Stop Second-Generation TKI (STOP 2G-TKI) study. 99 Patients in STOP 2G-TKI were required to have received 3 years of TKI therapy, with UMRD for 2 years, prior to attempting TFR; treatment was restarted following loss of MMR. The 48-month Kaplan-Meier-estimated rate of TFR in STOP 2G-TKI was 54%. TFR following dasatinib (in the second or later line following imatinib) was evaluated in the Dasatinib Discontinuation (DADI) trial; patients were required to have 1 year of BCR-ABL1 IS < 0.0069% prior to attempting TFR, and treatment was reinitiated upon detection of BCR-ABL1 IS 0.0069%. 94 The 36-month Kaplan-Meier-estimated TFR rate in DADI was 44%. Dasatinib cessation was also assessed in the DASFREE study of patients with 2 years of frontline or later-line dasatinib therapy, 1 year of confirmed MR 4.5, and a 1-log reduction in BCR-ABL1 transcript levels from baseline within 3-6.5 months of starting dasatinib. 95 Patients restarted therapy following loss of MMR, and the 12-month rate of event-free survival with no loss of 537 MMR was 49%. 538 22
539 540 In the ongoing ENESTfreedom trial, patients receiving frontline nilotinib were eligible to attempt TFR if they had achieved a sustained deep molecular response (defined as no assessments 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 worse than MR 4, 2 assessments between MR 4 and MR 4.5, and MR 4.5 on the final assessment before attempting TFR) during a 1-year treatment consolidation phase; 47% of patients remained in TFR at the data cutoff of the 144-week analysis. 88,89 For patients with TFR as a treatment goal who have been unable to achieve the required durable and deep molecular response with imatinib, data from ENESTcmr and ENESTop suggest that switching to a 2G-TKI, such as nilotinib, may allow them to improve their molecular response and become eligible to attempt TFR. 67,90,91 In ENESTcmr, patients who had not achieved a deep molecular response with long-term imatinib were more likely to do so by switching to second-line nilotinib rather than continuing imatinib. 67 In the ongoing ENESTop study, which assessed TFR in patients who had achieved and sustained MR 4.5 with second-line nilotinib only after switching from frontline imatinib (patients switched for various reasons including imatinib resistance [24%], imatinib intolerance [40%], or physician preference [36%]), 48% of patients remained in TFR by the data cutoff for the 144-week analysis. 90,91 Following these results from ENESTop and ENESTfreedom, TFR was added to the nilotinib label 102,103 and the NCCN revised their eligibility criteria for attempting TFR outside of clinical trials to no longer exclude patients based on a history of TKI resistance. 23 Thus, the increased rates of deep molecular responses achieved with 2G-TKIs vs imatinib may lead to more patients achieving TFR with these agents, although this has not yet been prospectively investigated. Nonetheless, in some ongoing clinical studies, patients are being switched from imatinib to 2G-TKIs for the purpose of achieving deeper molecular responses and, in turn, TFR (eg, ENESTgoal, 104 ENESTpath, 105 and SUSTRENIM 69 ). 562 563 564 Summary and the future of CML treatment The introduction of TKIs into the treatment paradigm for CML has transformed the course of therapy and greatly improved patient outcomes. 7,24,39,61-66,106 In turn, the effectiveness of these 23
565 566 TKI treatments has led to the development of disease-monitoring strategies that have changed over time and now allow most patients to have highly accurate and reproducible molecular 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 monitoring using peripheral blood rather than bone marrow sampling. In addition, achievement of earlier and deeper molecular responses is continuing to be integrated into CML treatment guidelines, and achievement of TFR is becoming a goal for many patients with CML. 23,25,78,103 Although 2G-TKIs may not improve overall survival beyond that achieved with imatinib, they can afford improved response rates and a reduced risk of progression to AP/BC 48,52 ; moreover, the improvements in deep molecular response rates with these newer TKIs may allow a greater number of patients the possibility for TFR. Because of this progress, the current management of CML-CP focuses on identifying 2 distinct patient populations. The first group consists of patients that are most likely to achieve a durable deep molecular response and become eligible to attempt TFR. The second group consists of patients for whom frontline or second-line therapy will fail, and who will require alternative therapies. Current trials of alternative therapies involve the new ABL1 TKI asciminib (formerly ABL001) 107-110 or combinations of BCR-ABL1 TKIs with agents that inhibit other pathways (pioglitazone [NCT02730195], ruxolitinib [NCT01702064 and NCT02973711], and axitinib [NCT02782403]). 111-114 Finally, immune pathway inhibitors would be worthwhile to test in patients with CML, and a phase 1 trial combining dasatinib with programmed death-1 inhibitors has started (CA 180-373). 115-117 Better methods are needed to help identify these 2 groups of patients. Currently, Sokal, Hasford, or EUTOS scores and bone marrow examinations that demonstrate non chronic- 588 589 590 phase CML are used to identify patients with higher-risk disease, who may benefit from treatment with a 2G-TKI rather than imatinib. 23,24 Additional biomarkers that predict treatment outcomes are needed. Two possibilities, BCR-ABL1 transcript type 118 and the presence of 24
591 592 additional cytogenetic abnormalities, 119 may prove valuable at predicting outcomes if the initial observations suggesting their usefulness are confirmed in larger numbers of patients. 593 594 595 596 597 598 599 600 601 602 603 604 605 CML is a unique disease driven by an oncogene whose enzyme product has been successfully targeted, resulting in the ability to effectively treat most patients with TKI therapy. However, the goal of limited-duration treatment and achievement of a cure remains a challenge. As newer agents and treatment strategies are developed, long-term outcomes, including quality of life and the potential to achieve TFR, will likely continue to improve. Acknowledgments Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Christopher Edwards, PhD, and Karen Kaluza, PhD, of ArticulateScience LLC for their medical editorial assistance with this manuscript. Authors had full control of the content and made the final decision for all aspects of this article. 25