Looking Beyond Overall Survival in Chronic Myeloid Leukemia

Harry Erba, MD, PhD

Chronic myeloid leukemia (CML) is one of the great success stories in anticancer therapy. The introduction of tyrosine kinase inhibitors (TKIs) transformed CML from a life-threatening disease to a chronic one for most patients. Although CML remains incurable without a stem cell transplant, the life expectancy for a patient with newly diagnosed disease today approaches that of the general population.¹ The result, said Harry P. Erba, MD, PhD, moderator of an OncLive Peer Exchange^® panel on current strategies for managing CML, is that the prevalence of CML is rising. One study estimated the prevalence of CML at 70,000 in 2010 and predicted it would increase to 112,000 in 2020, with further increases every decade thereafter before peaking at 181,000 in 2050.²

Figure 1. Clinically Relevant Thresholds of BCR-ABL1⁶

Optimizing Outcomes With Proper Monitoring

For a small subset of patients with CML, TKIs are ineffective or intolerable, whereas patients for whom TKIs are effective have historically been faced with the prospect of lifelong therapy. As investigators continue to look for ways to improve outcomes for the growing number of patients with CML, the primary goal has shifted from improving overall survival (OS) to helping patients achieve treatment-free remission (TFR). During the 90-minute OncLive Peer Exchange^® panel, Erba and panelists Michael J. Mauro, MD, and Jorge E. Cortes, MD, discussed how new data on TFR and updated guidelines for monitoring patients have influenced their approach in the clinic.Cortes started the discussion of monitoring by noting that although “close monitoring is critical to optimize benefits [of TKI therapy],”³ only 30% of patients with CML in the United States receive molecular monitoring at the appropriate intervals after starting a first-line TKI. He said failure to monitor patients appropriately prevents clinicians from identifying patients who respond poorly to the initial TKI while time remains to affect outcomes.

The panel agreed that real-time quantitative polymerase chain reaction (qPCR) for BCR-ABL1 transcript levels and bone marrow cytogenetic testing is standard for assessing treatment response and should be measured at diagnosis to provide a baseline comparison.^4,5 Cortes said recommendations from the European LeukemiaNet (ELN), the National Comprehensive Cancer Network (NCCN), and other major organizations for subsequent monitoring of BCR-ABL1 transcript levels once patients start TKI therapy are similar: every 3 months until the patient achieves a stable major molecular response (MMR) and every 3 to 6 months thereafter.^4,5 He said, at a minimum, every patient should have BCR-ABL1 transcript levels measured at 3, 6, 12, and 18 months after starting a TKI. “I think once a patient has a very stable MMR, every 6 months is fine,” Cortes said.

Erba noted there has been a shift in how molecular response (MR) is measured. Today BCR-ABL1 levels are reported using International Scale (IS) percentages, which correspond with the log reduction in BCR-ABL1 from baseline (Figure 1).⁶ MR is expressed as BCR-ABL1% on a log scale, where 10%, 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a decrease of 1, 2, 3, 4, 4.5, and 5 logs, respectively, below the standard baseline that was used in the study. Using the IS, ELN defines an MMR as a BCR-ABL1 expression of ≤0.1% (MR3.0 or better) and a deep MR as MR4.0 or MR4.5 (BCR/ABL1 expression ≤0.0032%).⁴ Erba explained that NCCN and ELN monitoring recommendations were based on findings from a retrospective study of 282 patients with CML treated with imatinib (Gleevec) between 2000 and 2010 that showed “the BCR-ABL1 to ABL ratio at 3 months was informative regarding progression- free survival [PFS] and OS.”⁷ The 8-year OS and PFS rates for patients who had a BCR-ABL1 transcript level above or below 9.84% were almost identical: 93.3% for patients with a level ≤9.84% versus 56.9% for patients with a level >9.84% (P <.001 for both comparisons).⁷

When to Switch to a New Tyrosine Kinase Inhibitor

Because laboratories differ in how they quantify BCR-ABL1, Mauro advised clinicians to use the same laboratory each time. Cortes pointed out that might not eliminate discordant results because results within an individual laboratory can vary for reasons outside the laboratory’s control, such as sample degradation. “Therefore, I think I can speak for all of us [by saying] that we should never act on 1 sample…You always want to confirm and look at trends and changes rather than just 1 individual sample,” he said.Initial therapy for many patients with CML is imatinib. Mauro said data from the TIDEL-II trial suggest that within 5 years, “you’re going to wind up switching at least a third of patients” to another TKI.⁸ The options are dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif), which all are FDA approved for patients with newly diagnosed Philadelphia chromosome—positive chronic CML as well as those who have developed resistance to imatininb.

With no head-to-head comparisons of second-generation TKIs, the panel agreed clinicians should consider subtle differences in safety between the agents when choosing. Mauro said the real debate is when to switch. He said his threshold for switching is low and includes patients who have not had an MR by 3 months. Mauro said primary resistance is rare and troubling and wondered why anyone would hesitate to switch a patient from imatinib to a secondgeneration TKI when other patients are given second-generation TKIs as first-line therapy. Erba said he believed second-generation TKIs are superior to imatinib, producing faster, deeper responses, and questioned whether it made more sense to start with a second-generation TKI. “In every single trial of interferon and the ABL TKIs, the highest rates of progression occurred in the first 6 to 12 months. My feeling is that, especially for the higher-risk patients… start with your best drug,” Erba said.

Cortes generally agreed with Erba. He said that although imatinib is a good drug and possibly safer for patients with an elevated risk of thrombotic events, “if I have CML, and I come to you, please give me a second-generation TKI.”

Mauro countered that results from the TIDEL-II study show how imatinib can be an excellent first-line option with an appropriate risk assessment and meticulous monitoring. In TIDEL-II, patients with newly diagnosed CML received initial treatment with imatinib 600 mg/day.⁸ Patients who did not meet molecular targets by 3 months were switched to nilotinib or had their dose of imatinib increased to 800 mg/day.⁸ By 5 years, 86% of all patients in the study had achieved MMR, 75% had achieved MR4.0, and 59% had achieved MR4.5. Cortes suggested the higher 600-mg/day median dose of imatinib may have increased the proportion of patients who achieved MR4.5 before switching to nilotinib.

Treatment-Free Remission

For patients with secondary resistance, Mauro said he looks at whether they had an early MR and considers “watchful waiting” if the patient had a deeper MR. “Sometimes mutation testing will give you important information,” he said.Achieving TFR is emerging as one of the primary treatment goals in CML. “This is not just giving patients a drug holiday…TFR is really a very active part of a patient’s therapeutic course,” Erba said. He noted that many studies involving thousands of patients had now looked at TKI discontinuation. He pointed out that “the duration that people have been on a TKI, the duration they’ve been in a deep response, how we define the deep response, and when you reinitiate therapy” vary among studies, which is why clinicians should follow NCCN guidelines. He stressed the importance of considering NCCN’s recommendation to obtain a second opinion from someone with expertise in treatment discontinuation (Figure 2).

Figure 2. Monitoring Response to TKI Therapy and Mutational Anaylsis⁵

Cortes explained how the STIM1 (N = 100) and TWISTER (N = 40) studies provided the foundation for current guidelines on TKI cessation.^9,10 Both studies enrolled patients who sustained deep MR for at least 2 years with first-line imatinib. After patients stopped imatinib, they were monitored closely. “In some of these studies, they did every month for the first year and then every 2 months and then every 3 months…They resumed therapy as soon as an qPCR became detectable,” Cortes said. In the TWISTER study, 47% of patients had stable TFR at 24 months, and most relapses happened in the first 6 months.10 Although 61 patients in STIM1 no longer had undetectable minimal residual disease 2.5 months after cessation, no patient experienced CML progression after a median of 6 years.⁹ All patients re-treated with a TKI achieved deep MR.⁹

“Re-treatment success through all the trials has been exceedingly high with regaining MMR and MR4.0 and MR4.5 at a very high rate—north of 90% to 95%,” Mauro said. He mentioned the EURO-SKI trial (n = 755), which is the largest trial to date of TKI discontinuation. 11 EURO-SKI included patients who used a TKI for at least 3 years and had a deep MR for at least 1 year.11 After treatment, molecular relapse-free survival was 61% at 6 months and 50% at 24 months. Mauro said patients, especially those treated with imatinib, likely need to be in deep MR for at least 3 years before stopping treatment, a goal he said means that a patient must probably use the frontline TKI for at least 5 years.

Cortes said varying definitions of deep MR in TFR studies (ranging from 4.0-, 4.5-, to 5.0-log reductions) and differences in the duration of deep MR make it challenging to determine “optimal requirements” for TFR. Cortes is an investigator for the US Life After Stopping TKIs (LAST) study, a prospective single-institution assessment of TKI discontinuation in patients with MR4.5 for at least 5 years.¹² He said LAST showed “patients who have a 5-year or longer duration of MR4.5 have a very low risk of relapse after treatment discontinuation— about 10% to 15%.” Sustaining deep MR longer was associated with better outcomes. Cortes said he was more comfortable with using MR4.5 as a threshold for discontinuing treatment because the relapse rate plateaued in the STIM1 trial, which used MR4.5, yet continued to increase in the EURO-SKI study, which used a threshold of MR4.0.

“I don’t know [whether] we have all the pieces of the puzzle yet, and I think there may be something different about the patients who do or don’t relapse…irrespective of the time and their depth of remission…,” Mauro said. He said the STIM1 trial found high-risk patients did not fare as well and identified Sokal risk score and duration of imatinib therapy as independent prognostic factors for molecular recurrence.⁹

Cortes said although he discusses discontinuing treatment with all patients “who have at least 2 years of a sustained MR4.5,” only 200 of them elected to stop therapy. He attributed patients’ reluctance to the strong emphasis placed on adherence and the permanence of treatment when introducing therapy. He advised clinicians to educate new patients about TFR when they begin a TKI and expressed optimism that the prospect of stopping it might cultivate better adherence.

“Putting some of these data in a drug label may actually be helpful for clinicians,” Erba said. He noted that the label for nilotinib was recently updated with findings from the phase II ENESTFreedom¹³ and ENESTop¹⁴ trials, which assessed TKI cessation in patients who had received first- or second-line nilotinib outside a clinical trial, respectively. In both studies, patients had to have used a TKI for at least 2 years. He said ENESTFreedom used “very strict criteria” for TFR. Investigators required at least 3 years of TKI therapy; monitoring every 12 weeks during year 3; and 2 or fewer qPCR results between MR4.0 and MR4.5, with a final qPCR result of MR4.5. “Roughly 50% of patients at the first endpoint of the study of 48 weeks, and then at 96 weeks, and most recently at 144 weeks, have remained in TFR, meaning that they have not lost MMR,” he said.13,15 Highrisk patients and anyone with even 1 qPCR result greater than MR4.5 were more likely to experience molecular recurrence. Erba said, “The important part of this is that of the 50% of patients who relapsed…all of them got back in an MMR.” He said patients achieved MMR a median of 7 weeks after restarting a TKI, most reached MR4.5, and none progressed.

With the exception of requiring intolerance or resistance to first-line imatinib, ENESTop used the same enrollment criteria as ENESTFreedom but stricter criteria for TFR.¹⁴ Erba said the results were “remarkably similar” to those of ENESTFreedom, with approximately 50% of patients maintaining TFR 144 weeks after cessation.^14,16 For first-line patients, he said nilotinib should be restarted at the prior dose “if the patient loses MMR at any point—1 determination.” He recommended mutational analysis for any patient who has not regained MMR within 3 months of resuming nilotinib. He recommended greater caution with secondline patients, restarting them if they have at least 2 qPCR results below MR4.0. Mauro noted that in all the studies, prompt re-treatment with the same TKI is usually effective in restoring remission and preventing progression.

Conclusions

Trials have found that approximately 20% to 30% of patients experience what investigators have termed TKI withdrawal syndrome after stopping a TKI.^11,17 Cortes said the most frequent symptoms are musculoskeletal aches and pains, but patients have also reported fatigue, fevers, and other constitutional symptoms. Symptoms are typically mild and do not require intervention beyond a nonsteroidal anti-inflammatory agent. “We don’t understand how this works, but I think it is important that we discuss this with patients,” he said. Erba noted that withdrawal symptoms usually get better over time.As the discussion concluded, Cortes marveled that TFR is now possible. “We never thought we would be at this point…but it is real,” he said. He added that success in real-world implementation of TKI cessation depends on monitoring patients closely and managing their disease properly. “We have to manage them as if they were in clinical trials, which is essentially what the NCCN guidelines and the ELN guidelines tell you to do,” he said.

Mauro and Elba agreed. “It fortunately is a very good story and a disease we could treat really well. We just have to be meticulous,” Mauro said.

References

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