Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia

Caldemeyer, Lauren E.; Akard, Luke P.

doi:10.1080/10428194.2016.1198959

Cited by 12 publications

(7 citation statements)

References 70 publications

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“…Normalization of many immune cell populations early in the setting of TFR and MolR, at least by 3 months following the initial timepoint of TKI cessation, may be linked to the dynamic nature of the immune system as evidenced by its constant immune surveillance and the enhanced net effector immune responses and decreased PD-1 and immune suppressors observed in CML patients in DMR compared to diagnosis (12). Thus, longer follow-up of patients in all TFR studies is critically needed to determine how long patients will ultimately be able to maintain TFR (148). In this regard, immune monitoring may reveal an optimum threshold level of immune effector responses in which TKI cessation is more achievable and successful, which could prove especially informative for patients contemplating a second TKI discontinuation attempt following initial failure.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

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Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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“…Accordingly, treatment-free remission (TFR) has become a treatment goal for many patients with CML-CP in DMR. Typically, TFR is attempted in selected patients in the context of DMR, as measured by a reduction in BCR-ABL1 transcript levels on the International Scale (IS), ranging from 0.01% (MR 4 ) to 0.0032% (MR 4.5 ) to 0.001% (MR 5 ) [26]. Successful TFR has been demonstrated in several clinical trials, the majority of which have included patients discontinuing long-term imatinib treatment.…”

Section: Introductionmentioning

confidence: 99%

Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study

Shah

García‐Gutiérrez

Jiménez-Velasco

et al. 2019

Leukemia & Lymphoma

113

124

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Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N ¼ 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (median; p ¼ .0051), line of therapy (first line; p ¼ .0138), and age (>65 years; p ¼ .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.

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“…Several international studies thereafter confirmed that approximately 50% of patients with CML who have sustained DMR remained in TFR ≥1 year after stopping treatment 9‐14 . The duration of exposure to TKI and DMR duration before TKI discontinuation are considered the most relevant prognostic factors for the success of TKI cessation 15 . Consequently, the traditional recommendation for lifelong TKI therapy was recently dropped for patients with CML, and TKI cessation guidelines have been issued by international experts 16,17 …”

Section: Introductionmentioning

confidence: 99%

Low‐dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment‐free remission in chronic myeloid leukemia patients: Results of a retrospective study

Cayssials

Diaz

Gallego-Hernanz

et al. 2020

Cancer

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Background Long‐term treatment‐free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). In clinical practice, tyrosine kinase inhibitor (TKI) dose reductions can be considered a means of preventing adverse effects and improving quality of life. We hypothesized that administration of low‐dose TKIs before treatment discontinuation does not impair TFR in patients with CML who have a deep molecular response (DMR, ≥MR4). Methods We conducted a retrospective analysis of 77 patients with CML who discontinued treatment with TKIs. Twenty‐six patients had been managed with low‐dose TKIs before stopping treatment. Patients were to be exposed to TKIs for ≥5 years and to low‐dose TKIs for ≥1 year and in DMR for ≥2 years. The loss of major molecular response (MMR) was considered a trigger for restarting therapy. Results In the low‐dose group, 61.5% of patients received second‐generation TKIs, and dose reduction was ≥50% for 65.4% of patients. With a median follow‐up of 61.5 months, TFR at 12 months was 56.8% in the full‐dose TKI group and 80.8% in the low‐dose group, and TFR at 60 months was 47.5% and 58.8%, respectively. The median time to molecular recurrence (≥MMR) from TKI discontinuation in the entire cohort was 6.2 months. All patients quickly achieved MMR after resuming TKI therapy. Results appear independent of both dose reduction and potential pretreatment with interferon‐α. Conclusion This retrospective study shows that TFR was not impaired by low‐dose TKI regimens before TKI cessation in Patients with CML. Nevertheless, prospective randomized clinical trials must be undertaken to analyze the probability of successful TFR in patients managed with TKI dose de‐escalation strategies before TKI discontinuation.

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Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia

Cited by 12 publications

References 70 publications

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study

Low‐dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment‐free remission in chronic myeloid leukemia patients: Results of a retrospective study

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