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Chronic Myeloid Leukemia Treatment

CME

Chronic Myeloid Leukemia: Optimizing Use of TKIs to Individualize Treatment Across the Disease Spectrum

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 15, 2024

Expiration: February 14, 2025

Fadi Haddad
Fadi Haddad, MD
CME/CE Information

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Case 4: A Patient With Suboptimal Response to Frontline Therapy

For the next case, let’s consider a 57-year-old woman with a history of depression, anxiety, and hypothyroidism who was diagnosed with high-risk chronic-phase CML and managed with nilotinib for 1 year. Measurement of response showed BCR::ABL1 transcript levels of 20%, 13%, and 5% at 3 months, 6 months, and 12 months, respectively. This woman is having a suboptimal response to nilotinib therapy. Given this, the first step is to evaluate adherence, as consistent adherence improves survival and reduces the risk of CML relapse.

Before confirming that a patient with CML has developed TKI resistance, ascertain whether he or she has been adherent to the treatment, and consider potential drug–drug interactions.

As knowledge of therapy in CML has evolved, it has been observed that switching frontline TKIs was done more frequently in the past for patients experiencing AEs, rather than attempting other approaches such as lowering the dose. Recent studies, such as some of the ones described previously have shown that lower doses of dasatinib, nilotinib, and ponatinib can be used safely, and with good efficacy.2 Thorough assessment and judicious change of therapy may help patients remain on frontline therapy longer.

Lack of adherence could be a major cause for suboptimal response. If adherence is confirmed, then it is recommended to perform a bone marrow biopsy to evaluate if progression to a more advanced form of CML has occurred, and to look for ABL1 kinase domain mutations. In this case, the patient was found to be adherent. The presence of an E255V mutation was detected on the bone marrow biopsy. This mutation is known to cause resistance to nilotinib. The patient was changed to dasatinib 100 mg daily and achieved a BCR::ABL1 transcript of 0.7% after 3 months of dasatinib therapy.

Prognostic Implications of Select Cytogenetic and Molecular Responses

Cytogenetic and molecular responses are key to guiding therapy choices in CML. A CCyR is defined as having no Ph chromosome in 20 metaphases (or a BCR::ABL1IS  ≤1%).2,19 This can be assessed by chromosome banding analysis or FISH. Achieving a CCyR is the gold standard for response because it is associated with improved survival; in one study, 5-year OS rates were 97% with CCyR vs 74% with no CCyR.29 This is also why therapy typically isn’t changed unless a patient loses a CCyR.

An MMR is associated with improved survival, but that is because it also includes CCyR. Achieving MMR for patients who have a CCyR does not improve OS, but it is associated with an improvement in progression-free survival (PFS).30,31 Deeper molecular responses, for example, MR4 (BCR::ABL1IS ≤0.01%) and particularly MR4.5( BCR::ABL1IS ≤0.0032%) are important considerations for TFR.

Early molecular response (EMR) is defined as ≤10% BCR::ABL1 transcripts at 3 months and is associated with improved PFS and OS with frontline therapy; 5-year PFS and OS rates with EMR compared with no EMR are as high as 99% vs 72% and 99% vs 79%, respectively.

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DASCERN: Change to Dasatinib Following Suboptimal Response to Imatinib at 3 Months

To date, it remains unclear what to do if a patient does not achieve EMR at 3 months. The phase IIb DASCERN study was designed to assess outcomes of an early switch to dasatinib compared with continuing on imatinib.32 Eligible patients were aged ≥18 yr with Ph chromosome–positive CML in chronic phase and with CHR, but with 3 mo BCR::ABL1 >10%IS after receiving imatinib. Primary endpoint was MMR at 12 months.

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DASCERN 5-Year Results: MMR and MR Outcomes With Dasatinib vs Imatinib

Results from DASCERN demonstrated that an early change in therapy to dasatinib can improve MMR at 12 months compared to remaining on imatinib (29.9% vs 14%; P = .005).32 At 60 months of follow-up, the cumulative MMR rate was higher in patients receiving dasatinib vs imatinib (77.0% vs 44.2%), but no PFS or OS benefit is evident.

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Predictors of Long-term Outcome to Second-Generation TKIs in Patients With CML

Multiple studies of second-generation TKIs in CML have shown significant benefit for achieving a CCyR at 3 months, as shown in these event-free survival and OS curves.33 Patients who reach these responses early on have a better probability of survival.

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When to Consider Changing Therapy

It is critically important for physicians to be able to distinguish between a response that is a treatment failure and a response that is a warning but without failure. Guideline recommendations are available from the European LeukemiaNet and the National Comprehensive Cancer Network.19,34

This table provides guidance on when to consider taking action to change therapy over time. Treatment failure is defined as any timepoint when a change in therapy is clearly indicated, for example, if a patient has no hematologic response at 3 months and then has transcripts >10% at 6 months. Patients whose treatment is failing may be able to switch TKIs and may be candidates for allogeneic stem cell transplant, and a bone marrow examination might be warranted to reassess CML phase and clonal evolution, plus the BCR::ABL1 mutational profile.

By contrast, the warning category represents patients who need to be more closely monitored but who do not necessarily need a change in therapy. However, these patients should be prepared to change therapy, and physicians should assess their treatment adherence and the potential for drug–drug interactions.

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ASC4MORE 96-Week Follow-up: Asciminib Add-On + Imatinib vs Imatinib vs Nilotinib

Another question that arises is how to manage patients who have not achieved DMR after 1-2 years of imatinib. The ENEST-Complete Molecular Remission (ENESTcmr) was an open-label, randomized, phase III trial which evaluated a switch from imatinib to nilotinib in patients with CP-CML with CCyR but without a DMR on long-term imatinib.35 Patients (n = 207) were randomized to change to nilotinib or remain on imatinib. At 48 months, MR4.5 was achieved in 53.8% and 44.7% of patients in the nilotinib and imatinib arms, respectively. It is noted that 13 patients in the imatinib arm achieved MR4.5 after crossover to the nilotinib arm.

More recently, the ASC4MORE trial evaluated the addition of asciminib to imatinib compared to imatinib or nilotinib in adults with CP-CML having received imatinib for at least 1 year, without DMR or treatment failure.36 Patients (n = 84) were randomized to 4 arms: a) continued imatinib, b) imatinib with asciminib 40 mg, c) imatinib with asciminib 60 mg, or d) nilotinib. At Week 96, more patients achieved MR4.5 with combination therapy then with continuing imatinib or switching to nilotinib. There were no unexpected safety findings in the combination therapy arms. The authors suggested that the high rates of DMRs warrant further study of combination therapy.

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Which of the following criteria is indicative of BCR::ABL1 TKI treatment failure according to guidelines and would cause you to recommend a switch in therapy?

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