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Long-term CML management requires routine assessments for toxicities, adherence
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Since the introduction of tyrosine kinase inhibitors, chronic myeloid leukemia incidence has doubled.
An estimated 32,000 Americans were living with CML in 2012. As oncology practices see more patients with CML, treatment advances that have dramatically extended survival will require longer follow-up periods.
This article will review the current knowledge about long-term follow-up of these patients.
Monitoring response
Debbie Blamble
Most patients treated with TKIs will achieve a complete cytogenetic response (CCyR). At that point, patients with CML can be monitored using peripheral blood samples. Specifically, BCR-ABL1 transcript levels can be measured using real-time quantitative polymerase chain reaction (qPCR) to establish and follow the molecular response. Repeat bone marrow biopsy for cytogenetics would only be necessary in the evaluation of a potential treatment failure.
An important consideration in molecular monitoring is to ensure that the BCR-ABL1 transcript levels are reported using the international scale (IS), which helps to standardize reporting and improve comparability of results between laboratories.
Long-term molecular monitoring is important for several reasons, including detecting late treatment failures, evaluating medication adherence and assessing eligibility for a discontinuation clinical trial, if available. Two guidelines on CML management — those from the National Comprehensive Cancer Network and the European LeukemiaNet (ELN) — have similar recommendations for long-term monitoring of these patients.
NCCN recommends qPCR every 3 months for 3 years after obtaining a CCyR, and then every 3 to 6 months thereafter. ELN recommends qPCR every 3 months until a major molecular response (MMR) is achieved, then every 3 to 6 months thereafter. qPCR should be repeated in 1 to 3 months if there has been a 1-log — or a five- to 10-fold — increase in BCR-ABL1 transcripts compared with the previous value.
The definition of MMR has changed over time. It was initially defined in the IRIS trial as a 3-log or greater reduction in BCR-ABL1 transcripts. More recently, molecular responses are reported as a percentage (BCR-ABL1/control gene). So MMR is now defined as BCR-ABL1 ≤0.1%. MMR also may be referred to as MR3.
Deeper molecular responses, including complete molecular response (CMR), also have been re-defined:
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MR4 = ≥4-log reduction, or ≤0.01%, BCR-ABL1 by IS;
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MR4.5 = ≥4.5-log reduction, or ≤0.0032%, BCR-ABL1 by IS
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MR5 = 5-log or greater reduction, or ≤0.001%, BCR-ABL1 by IS; and
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CMR = ≥5-log reduction, or undetectable, BCR-ABL by IS.
The definitions for deep molecular responses may continue to change as the community that treats CML focuses on standardizing response definitions and laboratory methods to detect BCR-ABL1 transcripts, particularly when present at low levels.
Adverse effects
Adverse effects can occur with any TKI. Hematologic adverse effects tend to occur early in the course of therapy, and they frequently are less problematic long term.
However, there are many nonhematologic adverse effects that can occur at any time or persist for as long as the patient remains on therapy. They include fluid retention, gastrointestinal disturbances, fatigue, laboratory abnormalities and musculoskeletal complaints, as well as cardiac toxicities (Table 1).
There are several strategies to help manage adverse events. Supportive measures may be suggested. Alternatively, drug holidays or dose reductions may be required. Drug-drug interactions should also be evaluated as a cause of new or worsening adverse effects.
In some situations, patients may need to switch TKI due to intolerance, which can be defined as one or more of the following:
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Any life-threatening grade 4 non-hematologic toxicity;
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Any grade 3 or grade 4 nonhematologic toxicity that recurs despite dose reduction or optimal supportive measures;
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Any grade 2 nonhematologic toxicity that persists for more than 1 month despite optimal supportive measures; or
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Any grade 3 or grade 4 hematologic toxicity that is unresponsive to optimal supportive measures and would require dose reductions below the minimal effective dose.
There may be patients who experience one or more effects that do not meet any of the above criteria but still affect the patient’s quality of life. Those patients also could be considered intolerant to their current TKI and require a change in therapy.
Having five agents commercially available in the United States gives providers the ability to select another agent with a lower risk of the adverse effect being experienced by the patient. Additionally, it will be interesting to see how or if the adverse-effect profiles of these agents change as patients remain on therapy for decades.
Adherence
Lack of adherence is a well-known problem in patients with chronic conditions that require long-term medication therapy. Several studies have demonstrated nonadherence as high as 25% to 35% in patients with CML.
The ADAGIO study by Noens and colleagues was a prospective, observational trial that looked at several measures of adherence and outcomes in patients with CML on imatinib (Gleevec, Novartis). Looking at pill counts, patients with suboptimal response had significantly higher mean percentages of imatinib doses not taken than patients with an optimal response. Researchers also found that nonadherence is more common than providers may believe and, therefore, should be assessed regularly, particularly in the setting of suboptimal or loss of response.
Ibrahim and colleagues used a medication event monitoring system to assess adherence during a 3-month period. Patients had been on imatinib for a median of 5 years. An adherence rate of ≤85% or failure to achieve MMR were the only independent predictors of loss of CCyR and imatinib failure. However, nonadherence appeared to be the most important factor, as patients who failed to achieve MMR but had good adherence had a prognosis similar to that of the MMR patients.
A study by Marin and colleagues demonstrated that adherence was a major factor in determining which patients achieve a molecular response. Improving adherence requires providers to routinely talk to patients about taking their TKI as prescribed, including expectations of therapy and barriers to adherence.
Data on discontinuation
There may be several reasons why patients and providers may wish to discontinue or temporarily suspend TKI therapy, such as adverse effects or a patient’s desire to have children. Use of TKIs during conception and pregnancy is not recommended. Patient selection will be an important factor in the success of any discontinuation strategy.
Several prospective studies have evaluated imatinib discontinuation in patients with sustained deep molecular responses. They include the French STIM studies — one by Mahon and colleagues, the other by Rousselot and colleagues — and the Australasian TWISTER study by Ross and colleagues.
In the Stop Imatinib (STIM) studies, more than 100 patients who had achieved a CMR for at least 2 years had their imatinib discontinued. Approximately 60% of patients lost their CMR, most within the first 6 months. All of these patients were able to achieve a decrease in BCR-ABL1 transcripts after reinitiating a TKI. In the most recent study, one patient suddenly transformed to blast crisis after again achieving an MMR. In summary, with a median follow-up of 17 to 31 months (range, 1-92), about 40% of selected patients are able to remain in CMR after discontinuing imatinib.
The TWISTER study evaluated the outcomes of 40 patients who had achieved undetectable minimal residual disease (UMRD) for at least 2 years on imatinib therapy. UMRD in this study was equivalent to MR4.5. After a median follow-up of 42 months, 55% of patients had a molecular relapse after discontinuation of imatinib. The majority of the relapses (68%) occurred within the first 6 months. All patients who relapsed were able to obtain at least an MMR. Similar to the STIM studies, approximately 40% of selected patients were able to remain with UMRD, or MR4.5, after imatinib discontinuation.
There are limited data that suggest better results (ie, more patients able to remain off therapy without relapse) may be obtained with the second-generation TKIs. Despite the evidence that shows a percentage of patients who discontinue TKIs may remain off therapy without molecular relapse, routine discontinuation of TKIs in patients with a sustained deep molecular response is not recommended outside of a clinical trial.
Conclusion
Long-term management of patients with CML presents several unique challenges.
Molecular monitoring is required to detect loss of response or nonadherence. Current recommendations suggest molecular monitoring at an interval not longer than 6 months. Providers will need to keep these patients engaged to maintain such close follow-up.
Additionally, long-term management of adverse effects will be important. Successful management of adverse effects is a critical component to maintaining adherence. Chronic adverse effects — even if low grade — can affect adherence, particularly if patients are not symptomatic from their CML (ie, the cure is worse than the disease).
Providers should routinely assess for toxicities and adherence. Because routine discontinuation of TKIs in responding patients is not recommended outside of a clinical trial, we are fortunate to have several TKIs to choose from for patients who are intolerant to a particular agent.
References:
Baccarani M. Blood. 2013;122:872-884.
Ibrahim AR. Blood. 2011;117:3733-3736.
Jabbour E. Leukemia. 2011;25:201-210.
Mahon FX. Lancet Oncol. 2010;11:1029-1035.
Marin D. J Clin Oncol. 2010;28:2381-2388.
Marin D. J Clin Oncol. 2014;32:379-384.
Noens L. Blood. 2009;113:5401-5411.
O’Brien S. J Natl Compr Canc Netw. 2013;11:1327-1340.
Oehler VG. Hematology Am Soc Hematol Educ Program. 2013;2013:176-183.
Ross DM. Blood. 2013;122:515-522.
Rousselot P. J Clin Oncol. 2014;32:424-30.
For more information:
Debbie Blamble, PharmD, BCOP, is an oncology clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center. She can be reached at The University of Texas MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Blvd., Houston, TX 77030; email: dblamble@mdanderson.org.
Disclosure: Blamble reports no relevant financial disclosures.