The discovery of the BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib in 2001 ushered in the era of targeted cancer therapies and revolutionized chronic myeloid leukemia (CML) treatment. For most patients with chronic phase (CP) CML, life expectancy is similar to age-matched peers.1 The current CML treatment arsenal includes imatinib; the second-generation (2G) TKIs dasatinib, nilotinib, bosutinib, flumatinib (China), and radotinib (South Korea); the third-generation (3G) TKI ponatinib; and the allosteric inhibitor asciminib. TKIs are associated with treatment-emergent adverse events (TEAEs) and for some, serious toxicities (Figure 1).2–10 A more comprehensive review of TEAEs and management is provided in a recent publication.11 Factors influencing therapy selection in individual patients include disease risk and the presence of comorbid conditions that impact tolerability and risk for specific toxicities. The use of patient-reported outcomes (PROs) has also begun to define the impact of TKI use on health-related quality of life (HRQoL), with most patients reporting HRQoL impairment.12–15 In efforts to help mitigate TEAEs and risks, expert panels such as NCCN now address lower-dose therapy and dose reduction.16 Given that many patients either do not become eligible for or fail TKI discontinuation, dose reduction can be critical in optimizing QoL for patients with CML. This article reviews data from nonrandomized studies, retrospective analyses, and prospective studies examining the impact of dose reduction or preemptive lower-dose therapy on TEAEs and efficacy. However, given outstanding outcomes for patients with CP-CML, caution is warranted. Select studies are discussed and all reviewed studies are summarized in Table S1 in the supplementary materials (available online with this article).
TKI-associated TEAEs of interest (all grades). Most TEAEs of interest were extracted from first-line clinical trials (and dosing) that led to FDA approval. TEAE incidence is based on a combination of initial trial and final follow-up trial data. TEAE incidence includes all severity grades when available. The IRIS study of imatinib also included >10-year follow-up, but details on TEAEs are more limited in this publication and we report earlier trial data. For treatment-emergent AOEs, we reference 10-year ENESTnd updates for nilotinib and OPTIC data for ponatinib. When trial data is unavailable, we include prescribing information. We acknowledge that incidence rates vary between studies, including those for the same drugs in later-therapy lines.
Abbreviations: ALT, alanine transaminase; AOE, arterial occlusive event; AST, aspartate transaminase; TEAE, treatment-emergent adverse event; TKI, tyrosine kinase inhibitor.
aBased on nilotinib 300 mg twice daily cohort.
Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.7044
When May TKI Dose Reduction From Recommended Dosing Be Considered?
NCCN, the European LeukemiaNet (ELN), and prescribing information provide guidance on dose reductions in the setting of specific TEAEs.16,17 However, chronic TEAEs can compromise QoL.12–15 In the US Life After Stopping TKIs study, participants in treatment-free remission (TFR) reported improvements in fatigue, depression, diarrhea, sleep disturbance, and social function, which worsened with TKI restart.18,19 Consequently, when discontinuation is not feasible, an important clinical question is whether dose reduction without re-escalation compromises outcomes.
Imatinib
The recommended imatinib dose for patients with CP-CML is 400 mg daily. Frequent TEAEs include fatigue, nausea, diarrhea, muscle cramps, fluid retention, transaminitis, and rash.20 Data from the phase II Japan Adult Leukemia Study Group (JALSG) CML202 study of 481 patients reported no differences in overall survival (OS) and event-free survival (EFS) when comparing patients receiving 400 mg versus 300 mg daily.21 However, dose reductions to <300 mg daily were associated with inferior response rates and survival outcomes.
In contrast, for patients with deeper molecular response such as MR4 (BCR::ABL1 ≤0.01% IS) or MR4.5 (BCR::ABL1 ≤0.003% IS), smaller retrospective studies have supported that dose reductions or intermittent imatinib dosing are feasible and generally safe.22,23 A single-center study of 43 predominantly low- or intermediate-risk patients examined outcomes after dose reduction to 300 mg daily.24 The median duration of MR4 was 4.1 years (range, 2.2–5.9 years) before dose reduction. At 36 months, 30 (69.8%) patients were in MR5 (BCR::ABL1 ≤0.001% IS), 9 (20.9%) in MR4.5, 3 (7.0%) in MR4, and 1 (2.3%) in major molecular response (MMR; BCR::ABL1 ≤0.1% IS). TEAEs improved from baseline in 62.2% and almost all reported complete symptom resolution. In patients with imatinib-related anemia, 12 of 13 patients had an improvement in red cell indices.
Prospective data supporting durable response after TKI dose reduction for patients in MMR or MR4 are provided by the DESTINY study.25,26 This multicenter, phase II cohort trial enrolled 174 patients with CP-CML treated predominantly with imatinib (n=148), but also included patients receiving dasatinib (n=10) or nilotinib (n=16). Enrollment criteria included treatment with TKI for ≥3 years and stable MMR or MR4 for ≥12 months. The median duration of TKI use was 7.7 and 6.5 years in the MMR and MR4 cohorts, respectively. Imatinib dose was reduced to 200 mg once daily, dasatinib to 50 mg once daily, and nilotinib to 200 mg twice daily and continued for 12 months. The primary endpoint was the proportion of patients who could first de-escalate treatment of 12 months and then discontinue treatment without losing MMR for a further 2 years. In an interim analysis, the durability of response after dose reduction was best in patients in the MR4 cohort versus the MMR cohort, with only 3 (2.48%) versus 9 (18.75%) patients losing MMR, respectively (P=.0007).25 TEAEs including lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning improved during the initial 3 months after dose reduction. All patients with molecular recurrence re-achieved MMR or deeper molecular responses after resuming full-dose TKI. Dose reduction did not compromise successful TKI discontinuation in patients in the MR4 cohort.26
Another approach to dose reduction is intermittent dosing. The INTERIM multicenter, phase II prospective study examined 76 older patients with CML (age ≥65 years) treated with first-line imatinib for ≥2 years and with stable complete cytogenetic response (CCyR; approximately equivalent to BCR::ABL1 ≤1%).27 Most (81%) had received imatinib 400 mg daily. The intermittent dosing schedule was 1 week on/1 week off for weeks 1 through 4; 2 weeks on/2 weeks off for weeks 5 through 12; and 1 month on/1 month off week 13 and thereafter. A total of 13 (17%) patients lost CCyR and MMR, and all but 1 regained CCyR and MMR at a median time of 7 and 6 months, respectively, after resuming continuous dosing. During the “on” months, no new or worsening of TEAEs was reported. TEAE resolution was seen in 11 of 20 patients. An ongoing phase III trial in patients aged ≥60 years, OPTkIMA, is evaluating the INTERIM approach (“fixed”) versus progressive intermittent dosing (longer periods off therapy in subsequent years) in patients receiving imatinib, dasatinib, and nilotinib.28,29
Dasatinib
The recommended dasatinib dose for patients with CP-CML is 100 mg daily. Common TEAEs include gastrointestinal side effects, pleural effusion, and skin rash.30 Pericardial effusion and pulmonary arterial hypertension are observed rarely. Pleural effusion rates increase with increasing dose and age.31,32 In patients treated with dasatinib on the first-line phase III DASISION study, pleural effusion occurred in 28% by 5 years, and in the CA180-034/dose-optimization study of dasatinib in later lines occurred in 28% of patients receiving 100 mg daily by 7 years.6,33 This toxicity combined with reports of efficacy after dose reduction prompted studies examining lower doses preemptively.34,35 Data from the DESTINY study support dose reduction in patients with MMR or deeper responses, and the ongoing OPTkIMA study is also examining intermittent dosing in patients treated with dasatinib.25,26,28,29
Nilotinib
The recommended nilotinib dose is 300 mg twice daily for patients with newly diagnosed CP-CML and 400 mg twice daily for resistant or intolerant CP-CML. TEAEs include rash, hyperglycemia, hyperbilirubinemia, hyperlipasemia, and QT prolongation.36 Nilotinib is also associated with an increased risk for arterial occlusive events (AOEs), which include cardiovascular, cerebrovascular, and peripheral arterial events. In retrospective reviews, events are reported in 10% to 25% of patients and the risk continues over time.37,38 At 5- and 10-year follow-up of the first-line randomized phase III ENESTnd study, AOEs were reported in 7.5% and 16.5% of patients receiving nilotinib 300 mg twice daily, 13.4% and 23.5% of patients receiving nilotinib 400 mg twice daily, and 2.1% and 3.6% of patients receiving imatinib, respectively.7,39 Published in abstract format, the NILO-RED observational study reported on outcomes for 81 patients after dose reduction in MMR, MR4, or MR4.5.40 After a median of 29 months of full-dose treatment, 13.4%, 25.4%, and 61.2% were in MMR, MR4, or MR4.5, respectively. Most patients (86.6%) were reduced to 450 mg once daily, whereas 10.4% were reduced to 400 mg daily and 3% to 300 mg daily. With a median duration of dose reduction at 24 months (range, 5–54 months), 6.3%, 16.4%, and 77.6% of patients were in MMR, MR4, or MR4.5, respectively. Two patients lost MMR while on reduced dose but regained deeper molecular response without intervention.
Bosutinib
The recommended bosutinib dose is 400 mg daily for newly diagnosed CP-CML and 500 mg daily in later lines. Gastrointestinal toxicities are extremely common (∼80% of patients) and are dose-related.41–43 In the first-line randomized phase III BFORE study, bosutinib dose reduction to 300 mg occurred in 30.6% of patients.8,42,44 After dose reduction, 45.1% achieved MMR and 17.1% maintained MMR for >6 months.44 TEAEs including diarrhea, thrombocytopenia, nausea, vomiting, and anemia decreased by >10%. A retrospective review of a phase I/II study of bosutinib in later lines also reported on the impact of dose reductions from 500 mg daily in 284 patients with CP-CML receiving bosutinib in the second line (CP2L) and 119 receiving bosutinib in the third line or beyond (CP3L).45 For CP2L patients, 83 (29.2%) were reduced to 400 mg daily and 50 (17.6%) to 300 mg daily. Among these patients, 42 (51%) achieved or maintained CCyR after dose reduction to 400 mg daily and 23 (46%) after dose reduction to 300 mg daily. For CP3L patients, 33 (27.7%) were reduced to 400 mg daily and 22 (18.5%) to 300 mg daily. Among these patients, 8 (24%) achieved or maintained CCyR after dose reduction to 400 mg daily and 7 (32%) achieved or maintained CCyR after dose reduction to 300 mg daily. Among evaluable patients in all cohorts, 33% and 24% achieved or maintained MMR in the 400-mg and 300-mg dose reduction cohorts, respectively. Notably, for patients that had achieved CCyR or MMR prior to bosutinib dose reduction, only 2% of CP2L and no CP3L patients lost this response. Across the entire patient cohort, dose reductions were associated with substantial decreases in diarrhea (Δ33% 400 mg, Δ54% 300 mg), nausea (Δ26% 400 mg, Δ29% 300 mg), and vomiting (Δ9% 400 mg, Δ23% 300 mg). No improvements in hematologic toxicities were seen.
Ponatinib
Ponatinib is a potent 3G-TKI indicated in later lines and for T315I-mutated CML. Black box warnings for ponatinib include AOEs, venous thromboembolic events, heart failure, and hepatotoxicity.38,46 TEAEs also include pancreatitis, hypertension, neuropathy, fluid retention, and impaired wound healing.46 A high rate of AOEs was reported in the phase II PACE study; however, other analyses suggested that the AOE risk is lower with lower ponatinib dosing.9,47,48 These observations led to the subsequent dose-finding phase II study, OPTIC.10 OPTIC evaluated 3 ponatinib dosing cohorts in patients intolerant or resistant to ≥2 TKIs or with a T315I mutation: 45 mg daily (cohort A), 30 mg daily (cohort B), and 15 mg daily (cohort C).10 In cohorts A and B, the dose was reduced to 15 mg daily when BCR::ABL1 was ≤1% IS. BCR::ABL1 ≤1% IS by 12 months was achieved in 52%, 36%, and 25% of patients in cohorts A, B, and C, respectively. For patients with T315I mutations, efficacy was strongly associated with starting dose, and BCR::ABL1 ≤1% IS by 12 months was achieved in 60% (cohort A), 25% (cohort B), and 11% (cohort C) of patients. Responses after dose reduction to 15 mg daily (median follow-up, 32 months) were durable and maintained in 73% and 79% of patients whose dose was reduced from 45 or 30 mg, respectively.10 Treatment-emergent AOEs were dose-dependent and highest in cohort A at 9.6%, versus 5.3% in cohort B and 3.2% in cohort C. A recent analysis estimated that response-adjusted dosing reduced the risk for AOEs by approximately 60%.49
When May Preemptive Dosing Below Recommended Dose Be Considered?
Starting lower-dose therapy and escalating based on response is an appealing strategy; however, one concern is that the ability to achieve optimal responses may be missed using this approach, which would compromise outcomes. It is these concerns that have resulted in a more thoughtful approach to dosing that diverges from prescribing information by NCCN and ELN. Emerging prospective and retrospective data with longer follow-up support successful outcomes on lower-dose therapy, although caution is warranted in high-risk patients with CP-CML.
Dasatinib
Retrospective studies of lower dasatinib dosing (50 mg and 70 mg) have supported efficacy and improved tolerance.50–52 Prospective data supporting a 50-mg daily dose in the first line comes from a US single-arm study of 81 patients with CP-CML, now with 5 years median follow-up.53–55 At 3 months, BCR::ABL1 transcripts decreased to ≤10% IS in almost all patients (96%), including 77% with transcripts ≤1% IS. At 12 months the cumulative incidence of CCyR was 94%, MMR was 79%, MR4 was 52%, and MR4.5 was 43%. At 60 months, cumulative response rates improved to 98%, 95%, 83%, and 82% for CCyR, MMR, MR4, and MR4.5, respectively.55 Patients were predominantly those with lower-risk CP-CML (65% low-risk and 29% intermediate-risk by Sokal score). To compare these results to a historical cohort, a propensity score analysis was performed.56 After matching baseline characteristics, similar rates of CCyR (97% vs 91%, respectively; P=.17) and MMR (81% vs 74%, respectively; P=.44) were observed in the low-dose versus standard-dose cohorts, respectively, at 12 months. There was no difference in EFS or OS. TEAEs were more common in the standard-dose versus low-dose cohort, and pleural effusion rates were 21% vs 5%, respectively (P=.02).
A recent prospective single-arm, multicenter study of older Japanese patients examined an extremely-low-dose approach.57 The DAVLEC study examined 52 patients with newly diagnosed CP-CML (age ≥70 years; median, 77.5 years) who received dasatinib initially at 20 mg daily with escalation at 3, 6, and 9 months based on treatment response and tolerability. At 12 months, 60% (31/52) achieved MMR, including 23 (44%) patients who remained on the 20-mg daily dose; additionally, 27% and 14% achieved MR4 and MR4.5, respectively. It is not yet known if this very-low-dose approach is as effective in patients of other ethnic/racial backgrounds, but these studies highlight the importance of careful studies in diverse patient populations.
Nilotinib
There are no prospective trials evaluating up-front lower doses in patients with newly diagnosed CP-CML receiving nilotinib. However, several retrospective reviews have assessed the safety of reducing nilotinib dose in later lines.58 The ENESTswift single-arm trial examined 20 patients who were switched to nilotinib due to intolerance, but not resistance.59 Patients started nilotinib at 300 mg twice daily. At any point over 24 months, 50% of patients achieved MR4.5. For patients who are intolerant of, but not resistant to, prior therapy, starting nilotinib at 300 mg twice daily may be appropriate.
Bosutinib
Because of high rates of diarrhea, nausea, vomiting, and elevations in serum transaminases and observed efficacy at lower doses, expert panels have recommended starting bosutinib at 200 to 300 mg daily and escalating the dose as clinically indicated.60 The phase II GIMEMA BEST trial examined 63 patients (age ≥60 years) who started reduced-dose bosutinib in the second line.61,62 Bosutinib was started at 200 mg daily for 2 weeks then increased to 300 mg daily. For patients with BCR::ABL1 transcripts >1% IS after 3 months, the dose could be increased further; 73% remained on 300 mg and 6% remained on 200 mg. At 12 months the MMR rate was 59%, and by 36 months the probability of achieving or maintaining MMR was 78%, MR4 was 54%, and MR4.5 was 46%. The incidence of gastrointestinal toxicity was lower than other reports.62 Another prospective study of step-in bosutinib dosing starting at 300 mg daily in the second or third line highlighted the gastrointestinal toxicities of higher-dose bosutinib, with 40% of patients not able to escalate to the recommended 500-mg daily dose.63 Although this study was terminated prematurely, overall efficacy was excellent, with 79% achieving MMR with a median dose of 387 mg daily. In contrast to other reports, the study did not report an improvement in gastrointestinal toxicities with step-in dosing.
Discussion
Most patients with CP-CML have a normal life expectancy.1 Consequently, the most important concern with dose reduction is compromising this outcome. However, TEAEs that impact HRQoL are frequent and, for many, appear to be dose-related.15,25 Additionally, specific toxicities such as pleural effusion and AOEs, which may result in permanent organ damage, also appear to be dose-related.10,31,49,55 Although TKI discontinuation is the ultimate goal, most patients remain on therapy for many years.64,65 The best starting dose for an individual patient is unclear. Ideally, an improved understanding of pharmacokinetics across racial and ethnic groups and identification of biomarkers of response and toxicity are needed. One approach to personalized dosing is therapeutic drug monitoring (TDM). A prospective study of patients with newly diagnosed CP-CML examined early stepwise dose reductions targeting a dasatinib trough level (Cmin) ≤3 nmol/L and found the incidence of pleural effusion was lower in the TDM arm versus the control arm, with no differences in molecular responses observed.66 To date, such approaches, although appealing, are not readily clinically available.
The summarized retrospective and prospective data support TKI dose reductions in specific scenarios. In the absence of durable MMR or deeper molecular responses, imatinib doses <300 mg daily are associated with poorer outcomes, and thus up-front doses <400 mg daily should be given cautiously with this less-potent TKI. For dasatinib initiated at 50 mg daily, long-term follow-up of a prospective pilot study supports similar efficacy with lower rates of pleural effusion.55 One caveat is that most patients in this study did not have high-risk CP-CML, and thus caution is warranted in these patients. Retrospective data have demonstrated higher toxicity with standard-dose dasatinib in older and in Asian populations.50–52 The prospective DAVLEC study provides evidence for very low dasatinib dosing in elderly Japanese patients, although whether these results translate to other ethnic or racial groups is unknown.57 For nilotinib, a starting dose of 300 mg twice daily in later lines (vs 400 mg twice daily) is reasonable, especially if therapy was switched due to intolerance rather than resistance.59 For bosutinib, expert panels have recommended starting at 200 to 300 mg daily and escalating as clinically indicated to limit premature discontinuation.60,62,63 Although outcomes for select patients are good, caution is warranted in high-risk patients with CP-CML. Emerging data regarding specific additional mutations present at diagnosis such as ASXL1 highlight a population in whom dose adjustments should be done cautiously, because these mutations can be associated with inferior molecular responses and poorer failure-free survival.67–69 For ponatinib, based on the OPTIC study, dose reduction to 15 mg daily should be considered when BCR::ABL1 is ≤1% IS to mitigate AOE risk but not compromise efficacy.10 Insufficient data for reduced asciminib dosing are currently available.
For younger patients, patients who tolerate full-dose TKIs, patients who strongly prioritize TKI discontinuation, and higher-risk patients with CP-CML, starting full dose may be an optimal strategy. Retrospective and prospective studies support that dose reduction for these patients when in MMR or deeper responses does not compromise response in most. In the DESTINY study, of predominantly imatinib-treated patients, loss of MMR after 50% dose reduction occurred in 19% of patients in MMR, but only 2% of patients in MR4.25 Dose reduction is also a reasonable approach prior to TKI discontinuation in patients with durable MR4 or MR4.5.26 An alternative to imatinib dose reduction is intermittent imatinib dosing, which offers the possibility of treatment-free days. The ongoing OPTkIMA study is examining both fixed and progressive dose reduction strategies and will provide further insights on intermittent dosing for other TKIs.29 For bosutinib-treated patients, the largest retrospective review reported that only 2% of patients taking bosutinib in later lines lost CCyR or MMR with dose reduction to 400 mg or 300 mg daily.45 For nilotinib-treated patients, the NILO-RED study supports dose reduction to 450 or 400 mg daily in patients with MMR or deeper responses.40 An important unanswered question is whether further dose reduction decreases AOE rates in these patients. An overview of our approach is provided in Figures 2 and 3.
Scenarios where lower-dose therapy may be considered either preemptively or in the setting of TEAEs.a
Abbreviations: AOE, arterial occlusive event; ELTS, EUTOS long-term survival; MMR, major molecular response; TEAE, treatment-emergent adverse event; TFR, treatment-free remission; TKI, tyrosine kinase inhibitor.
aFor patients with limited side effects, dose reductions may be considered; for example, prior to TKI discontinuation or for risk mitigation.
bCaution with 200-mg dose recommended.
cReduced dose in later-line in intolerant patients.
dThe DAVLEC study reported dasatinib 20 mg daily dosing in older Asian patients.
eThe UK DESTINY study examined dose reduction in patients with durable responses >12 months. Dose reduction decisions are influenced by duration/durability of MMR, desire to attempt TFR, and degree of side effects.
fPer the OPTIC study, ponatinib starting dose of 30–45 mg daily, 45 mg may be preferred for T315I mutations with dose reduction once BCR::ABL1 ≤1%. Dose reduction is recommended to reduce risk for AOEs.
gThe UK DESTINY study reduced imatinib dose to 200 mg daily, dasatinib to 50 mg daily, and nilotinib to 200 mg twice daily in patients with durable MMR or MR4 for >12 months.
hRetrospective review of front-line and later-line therapy supports bosutinib dosage of 300 mg daily.
iIn patients starting at dasatinib dose >50 mg daily.
jThe NILO-RED observational study reported on dose reduction to 400–450 mg daily.
kMay consider low dosing longer-term for patients who successfully regain deep molecular response after TKI discontinuation failure; limited data for very-low-dose TKI dosing in these settings.
Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.7044
Best practice: management after starting therapy at reduced dose.
Abbreviations: AE, adverse event; AOE, arterial occlusive event; ELN, European LeukemiaNet; MMR, major molecular response; TKI, tyrosine kinase inhibitor.
aResponse criteria based on NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Chronic Myeloid Leukemia, Version 2.202416 and ELN 2020 recommendations.17
bFor patients making dose reductions within the first 12 months of therapy before durable MMR or deeper molecular responses have been achieved, close monitoring at 3-month intervals is recommended to ensure molecular response is not lost.
cFor specific toxicities, a change in therapy rather than dose reduction is strongly recommended. These toxicities include AOEs, recurrent pleural effusions, pulmonary hypertension, severe hypertension (ponatinib) not responsive to antihypertensive therapies, enterocolitis, neurotoxicity, or immune-mediated adverse events, such as pneumonitis, hepatitis, myocarditis, pericarditis, or nephritis.71
dHematologic toxicities may persist after TKI switch.
Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.7044
Dose reductions overall appear to reduce TEAEs such as gastrointestinal toxicity on imatinib or bosutinib, rates of pleural effusion on dasatinib, and rates of AOEs on ponatinib. However, management of patients with moderate to severe cytopenias remains problematic and cytopenias often recur on lower doses. Furthermore, for some patients, serial intolerances across all lines of treatment can be seen.70 Lastly, for specific toxicities, including AOEs, pulmonary hypertension, and recurrent pleural effusion, a therapy switch is recommended rather than dose reduction (a full list is provided in Figure 3).71 In summary, TKI dose reduction is an increasingly important consideration within the CML treatment arsenal and should be considered prior to therapy switch. Close monitoring after dose reduction is critical so that normal life expectancy is not compromised.
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