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Less intensive blood monitoring safe for chronic myeloid leukemia
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Less frequent monitoring of BCR-ABL1 gene mutations did not negatively affect outcomes among patients with chronic myeloid leukemia, according to study results published in Cancer.
Discontinuation of first-line tyrosine kinase inhibitors after resistance or intolerance also appeared feasible, researchers reported.
“Although we were part of the national study that was looking at discontinuation of therapy in CML, we had our institutional preference to stop treatments in CML patients who met the criteria as previously published from European studies,” Vamsi Kota, MD, assistant professor of hematology/oncology at Winship Cancer Institute of Emory University, told HemOnc Today. “In addition, we had some patients who would not have qualified for the multicenter study that we wanted to discontinue therapy using our approach.”
TKIs have dramatically improved outcomes for patients with chronic phase CML. However, the appropriate duration of TKI therapy is unknown, and the concept of lifelong treatments with these oral agents has been challenged by several studies that demonstrated sustained treatment-free remissions among patients who discontinued imatinib after prolonged deep molecular remissions.
Patients typically are monitored closely after TKI discontinuation for the reappearance of BCR-ABL1 by blood testing monthly for 6 to 12 months, bimonthly for the next 6 to 12 months, and quarterly thereafter. However, the optimal frequency of molecular monitoring has not been established.
Typically, a blood test costs about $300, Kota said.
“In our opinion, there was also a psychological cost with frequent testing in terms of patients visiting a testing center, getting a test and then waiting for the results to come back,” he said.
Between January 2010 and September 2015, researchers reviewed records of 24 patients (median age, 56.7 years; range, 19.9-81.5) with CML who discontinued TKI therapy with imatinib (n = 16), dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka; n = 5) or bosutinib (Bosulif, Pfizer; n = 3) after achieving undetectable molecular residual disease for at least 2 years. Twenty-one patients had chronic phase CML, two had accelerated phase CML and one had lymphoid blast phase disease.
Researchers prospectively monitored patients on an intended schedule of blood quantitative reverse transcriptase polymerase chain reaction for BCR-ABL1. The schedule included testing monthly for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response, after which patients reinitiated the previously discontinued TKI.
Researchers performed blood quantitative reverse transcriptase polymerase chain reaction for BCR-ABL1 1.3 ± 0.7 times within the first 3 months (n = 24) and 2.7 ± 1.4 times in the following 12 months (n = 18).
Median follow-up was 36.5 months (range, 3.2-67.4).
Researchers calculated probabilities of treatment-free remission of 65.7% (95% CI, 55.8-75.6) at 1 year and 59.7% (95% CI, 49.1-70.3) at 2 years.
After TKI discontinuation, loss of major molecular response occurred among nine patients at a median of 2.8 months (range, 1.8-14.2 months).
Three patients reinitiated TKIs 7 months to 13 months after loss of major molecular response due to patient preferences or ongoing pregnancy. One regained deep molecular remission and the other two patients achieved complete cytogenetic remission after reinitiation of TKIs.
“As of now, the standard of care is to refer to a center with CML specialists that can monitor patients after discontinuation,” Kota said. “Even with the lower frequency of tests that we did, it still needs close monitoring. More importantly, we need to ensure that the patient is truly eligible for discontinuation of therapy.”
Researchers noted the study’s small sample size as a limitation.
“Despite the success of stopping treatment in approximately half the patients, the other half were patients who were interested in discontinuation but needed to restart therapy,” Kota said. “A second discontinuation approach is being explored now with ongoing trials with us, as well as other centers in the country.” – by Chuck Gormley
For more information:
Vamsi Kota, MD, can be reached at vamsi.kota@emory.edu.
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Michael J. Mauro
The paper from Kong and colleagues poses some provocative questions regarding the “who” and “how” to approach pursuit of treatment-free remission for patients with CML.
Ironically based on data culled before larger trials prompted development of “guidelines” for the type of patient and how to monitor, this series represents perhaps a more pragmatic real-world experience from the CML clinic, and the heterogeneous nature of patients seeking treatment-free remission.
The success rate, defined according to current standards — no loss of major molecular response after cessation — was as good or better than larger series of carefully selected patients. The series included a handful of patients with prior advanced-phase disease — not considered eligible for treatment-free remission — and also had intended monitoring less than recommendations suggest. Beyond intended, actual monitoring — again “real world” — was less than intended. Are these maneuvers safe as we now embark, after incorporation of treatment-free remission guidelines into National Comprehensive Cancer Network guidelines, into more widespread treatment-free remission attempts in the United States?
Despite inclusion of cases of resistance and disease progression, this series represents a cohort of patients with CML treated earlier in the tyrosine kinase inhibitor era who had lengthy TKI treatment and likely sufficient time in deep molecular remission to maximize chances of success. Their disease may not have been as complex as a contemporary population of patients with such events who may have had earlier exposure to more potent agents or later salvage agents, such as ponatinib (Iclusig, Takeda Oncology). There certainly will be demand and request for patients with prior resistance or moreover mixed resistance and intolerance to consider treatment-free remission; if change in therapy leads to long and deep remission similar to patients responding to first-line therapy, the “playing field” may be leveled, and treatment-free remission success may not differ as the authors propose. As treatment-free remission data likely will emerge for patients with varying degrees of resistance, such an assumption can be vetted more properly. Similarly, careful study of patients with prior advanced-phase disease is needed, as the number in this cohort is very small and selection bias may have played a role.
A more pressing question is that of monitoring requirements. Can we whittle away the monthly and bimonthly suggested molecular studies required to monitor a treatment-free remission patient? Although relapsing disease has consistently clustered very early — the overwhelming majority occur in the first 6 months — further study into the optimal monitoring requirement is needed. Although the cost of TKI therapy is shed during treatment-free remission, access and cost to molecular monitoring needs to be considered.
I applaud the authors of this paper for their work and shedding light on practical matters needing attention with regard to treatment-free remission. I especially would like to acknowledge the lifelong work and dedication, and the tragic loss in 2017 from his own battle with cancer, of the senior author, H. Jean Khoury, MD. His name, spirit, dedication and energy will live on through the H. Jean Khoury Cure CML Consortium, which he helped found and which, as an organization, took on treatment-free remission as its first academic collaborative clinical trial project — the LAST trial.
References:
Atallah E, et al. Abstract 2903. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
H. Jean Khoury Cure CML Consortium. Available at: curecml.org. Accessed on Dec. 18, 2017.
Kong JH, et al. Cancer. 2017;doi:10.1002/cncr.30608.
Mahon FX, et al. Abstract 787. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
National Comprehensive Cancer Network. NCCN guidelines for CML. Available at: www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed on Dec. 18, 2017.
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