CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 15, 2024
Expiration: February 14, 2025
Case 1: A Young Patient With Potential Consideration for TFR
For our first case, let’s consider a 31-year-old woman with no previous medical history who had routine laboratory testing that revealed an incidental white blood cell concentration of 35,000 cells/mcL. She underwent a bone marrow biopsy, and it was determined that she had chronic-phase intermediate-risk CML. For this young woman with newly diagnosed chronic-phase intermediate-risk CML, I would recommend a second-generation TKI. Treatment with a second-generation TKI in the frontline setting induces faster and deeper molecular responses compared to imatinib, and is preferred in young patients who are aiming for TFR. I would start this patient on dasatinib 50 mg orally daily. In a study of 83 patients with newly diagnosed chronic-phase CML, this reduced dose was shown to be associated with fewer AEs and comparable efficacy to the 100 mg dose.10
Frontline Treatment of Chronic-Phase CML: Risk Stratification
After patients, such as this one, are diagnosed with CML, they are typically stratified according to risk using one of the prognostic risk scores.2 The first with broad application was the Sokal score, which has remained valuable for parameters such as response to outcome after TFR. The Hasford score was developed primarily with the intent to be more predictive of outcomes with interferon after it was introduced. Both of these scores assign patients a low, intermediate, or high risk score. The Sokal and Hasford prognostic scoring systems, and the European Treatment and Outcome Study (EUTOS) long-term survival (ELTS), are based on some similar clinical elements such as age, spleen size, and the percentage of blasts. These risk category scores have remained predictive of outcomes with targeted therapies for CML even though they were developed before TKI therapy was introduced. For example, the high-risk Sokal patients have shorter overall survival (OS), as seen in the randomized IRIS study of imatinib vs interferon for frontline therapy.11 In later studies comparing second-generation TKIs to imatinib, risk-scoring systems have been predictive of the rate of MMR with nilotinib, dasatinib, and bosutinib, as well as decreased progression to the accelerated phase and blast phase.12 The risk category score obtained for an individual patient may affect selection of TKI in that a second-generation TKI may be favored in patients with higher-risk disease.2
In addition to identifying clinical factors to guide treatment, there has been increasing interest in developing new biomarkers and molecular features that can better define risk. It has been reported that some patients at the time of CML diagnosis may have mutations in genes that are associated with other cancers (eg, ASXL1, DNMT3A, TET2) that may predict a worse outcome.13 The ASXL1 gene is most often mutated at diagnosis. The clinical utility of testing for biomarkers at the time of diagnosis is still to be determined.
Prognostic Scoring Systems for CP-CML
This table shows the equations used to calculate the risk for an individual patient with chronic-phase CML. The Sokal and Hasford scoring systems were developed first. The most recently developed scoring system is ELTS, which was developed to predict the risk of CML-related death, despite the fact that most patients with CML receiving targeted therapy die due to other causes. Nevertheless, the ELTS system is useful to predict the risk of death due to CML, for example, by progression to the blast phase.
These scoring systems are predictive and remain in use. The Sokal system is the most widely used, although in Europe the ELTS is rapidly gaining momentum. Of note, online calculators are available here for each scoring system.
IRIS 10-Year Follow-up: Imatinib vs Interferon Plus Cytarabine in Newly Diagnosed CML in Chronic Phase
The agents with demonstrated efficacy in newly diagnosed patients in chronic-phase CML include imatinib, nilotinib, dasatinib, bosutinib, and asciminib. The phase III IRIS study helped define TKIs as the frontline standard of care in newly diagnosed CML. In this study (N = 1106), patients with newly diagnosed CML in the chronic phase were randomized to receive either imatinib or the standard of care at that time, interferon plus cytarabine.14 Results showed a significantly higher probability of major cytogenetic response (MCyR), defined as complete or partial (0%-35% Ph-positive cells in metaphase) response, which was a primary endpoint in trials more than 20 years ago. Although no survival benefit was evident initially, long-term follow-up at 10 years shows a modest but statistically significant survival benefit: 83.3% for imatinib vs 78.8% for interferon. This is remarkable given that the majority of patients on interferon crossed over to the imatinib arm, and most did so very early.
ENESTnd 10-Year Update: Cumulative Incidence of MMR in Chronic-Phase CML With Nilotinib vs Imatinib
Following IRIS, a series of studies were conducted to compare second-generation TKIs to imatinib. In the phase III ENESTnd trial, 846 patients with newly diagnosed, Ph-positive, chronic-phase CML were randomized to nilotinib at either 300 mg or 400 mg twice daily vs imatinib 400 mg once daily.15 The results established nilotinib 300 mg twice daily as a standard of care for frontline therapy, with 400 mg reserved for the salvage setting.
At 10 years, the incidence of MMR, as defined by reduction in BCR::ABL1 transcript in 0.1% of cells or less, was significantly higher for patients who received either dose of nilotinib compared with imatinib (~79% vs 63%, respectively). Likewise, the incidence of DMR, MR4.5 (molecular responses with a 4.5-log reduction in BCR::ABL1 transcript from baseline), at 10 years was 61% with nilotinib compared with 39% with imatinib.
DASISION 5-Year Update: MMR and MR Outcomes With Dasatinib vs Imatinib in Newly Diagnosed Chronic-Phase CML
MMR and MR4.5 were also evaluated in the phase III DASISION study of dasatinib vs imatinib in patients with previously untreated CML (N = 519).16 At 5 years of follow-up, both MMR and MR4.5 were significantly superior with dasatinib, with good separation between the curves. The cumulative rate of MMR was 76% with dasatinib vs 64% with imatinib (P = .0022). At 5 years, MR4.5 was also superior with dasatinib, at 42% vs 33% for imatinib (P = .0251). Clearly, dasatinib has not only superior benefit vs imatinib, but a longer duration of benefit as well.
Of importance, as seen in both ENESTnd and DASISION, not every patient will achieve an MMR, and certainly not MR4.5, but that is not necessarily cause to change therapy.
BFORE 5-Year Update: MMR and MR Outcomes With Bosutinib vs Imatinib in Newly Diagnosed Chronic-Phase CML
BFORE was a randomized, phase III trial comparing bosutinib 400 mg once daily to imatinib in 536 patients with newly diagnosed chronic-phase CML.17 As shown here, at 5 years, the comparison of bosutinib to imatinib was similar to the studies comparing nilotinib and dasatinib with imatinib. The cumulative incidence function for MMR was significantly higher for patients who received bosutinib compared with imatinib (HR: 1.34; 95%CI: 1.10-1.64). The results showed an early benefit of bosutinib in MMR rates and in the DMRs (MR4 and MR4.5).
ASC4FIRST 48-Week Update: Asciminib vs Investigator-Selected TKI in Newly Diagnosed Chronic Phase CML
Asciminib, the first-in-class STAMP inhibitor, received FDA accelerated approval for patients with Ph-chromosome–positive, chronic-phase CML previously treated with 2 or more TKIs, and Ph-chromosome–positive, chronic-phase CML with T315l mutation.8 In the recently reported ASC4First phase III trial, patients with newly diagnosed chronic-phase CML were randomized to asciminib or an investigator-selected TKI.18 The 2 primary endpoints of the trial were comparisons of MMR at Week 48 between asciminib and imatinib, or between asciminib and all investigator-selected TKIs.
ASC4FIRST: Molecular Responses With Asciminib vs IS-TKIs
At 48 weeks, the percentage of patients with MMR was significantly higher for patients who received asciminib compared with an investigator-selected TKI (67.7% vs 49%, respectively). Likewise, there was significantly higher MMR rate at Week 48 with asciminib compared to the preselected imatinib stratum. AEs of grade ≥3 observed with asciminib were mostly hematologic consisting of thrombocytopenia and neutropenia. However, the median follow-up of patients treated in the asciminib arm was only 16.3 months. Therefore, longer follow-up is needed for a better evaluation of the side effects profile of asciminib, in particular cardiovascular AEs.
Case 1 Continued: Young Female With Newly Diagnosed CML
Let’s return to our younger patient who started initial treatment with dasatinib. She achieved early molecular response (BCR::ABL1 transcript <10%) at 3 months of therapy and MMR at 6 months of therapy. At this time, she has been in MR4.5 for 2 years and wants to discuss whether she could stop her treatment or if she needs to continue. Studies on treatment discontinuation have established that a longer duration of MR4.5 was associated with a higher success rate of TFR. The rate of TFR increased from approximately 50% in patients with MR4.5 of 2 to 3 years, to more than 80% in patients with MR4.5 of 5 years or longer. Therefore, for this young patient, I would recommend continuing TKI therapy and attempting TFR after at least 5 years of MR4.5 to maximize her chances of success. However, if the patient is considering pregnancy at this stage, then I would offer her treatment discontinuation with close monitoring of her BCR::ABL1 transcript levels by polymerase chain reaction (PCR).
Select Trials of TKI Discontinuation at First Line
Discontinuing TKI therapy has increasingly become a goal of therapy for patients with CML, such as this one, who are maintaining DMR (MR4 or deeper response) for at least 2 years with TKI therapy.19 TFR is the patient’s ability to maintain remission after discontinuation of TKI therapy. Multiple studies have been conducted with discontinuation following imatinib, nilotinib, and dasatinib therapy demonstrating TFR rates of approximately 40% to 50% at 2 years. As many will relapse, there are specific criteria for identifying patients for consideration of this approach.
Discontinuation of TKI therapy after a DMR of 5 years or longer results in higher TFR rates (>80%) so some experts are recommending longer duration of TKI therapy before discontinuing.20 The MD Anderson retrospective study, the second largest TFR study reported, evaluated outcomes in 284 patients with Ph-positive, chronic-phase CML who discontinued TKI therapy. The median time from the start of frontline TKI to discontinuation was 117 months. At a median follow-up of 36 months, the estimated 5-year TFR rate was 79%. The success of TFR was higher in those who achieved MR4 or MR4.5 for 5 years or longer.
Discontinuing TKIs: Criteria and Monitoring
Specific criteria must be met to qualify for treatment discontinuation, and it is recommended that the patient meet all criteria for this approach.19 The criteria are that the patient (a) must have typical BCR::ABL1 transcripts at diagnosis (to allow assessment on the International Scale), (b) has received at least 2 years of TKI therapy, (c) has achieved a DMR such as MR4.5 for 2 to 5 years or longer, (d) agrees to frequent high-quality monitoring, and (e) has made the well-informed decision to stop therapy.
After treatment is stopped, the patient should be monitored monthly during the first 6 months, then every 2 months during the next 6 months, then every 3 months going forward. Approximately 50% to 80% of patients will achieve a successful TFR depending on the duration of DMR before treatment discontinuation. Almost all patients who lose MMR following treatment discontinuation regain response after resuming treatment with either the same or a different TKI.
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