|Year : 2022 | Volume
| Issue : 3 | Page : 126-131
Evaluation of tyrosine kinase inhibitor discontinuation initiative in patients with chronic myeloid leukemia at princess noorah oncology center
Afnan Mohammed Noor1, Mansoor Ahmed Khan1, Muteb M Al-Thomali2, Abdelmajid H Alnatsheh1, Ahmed A Absi2, Fahad M Hakami3, Majed A Alshamrani1
1 Department of Pharmaeceutical Care, Ministry of National Guard-Health Affairs, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
2 Department of Haematology, Ministry of National Guard-Health Affairs, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
3 Department of Molecular Medicine, Ministry of National Guard-Health Affairs, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
|Date of Submission||01-Oct-2021|
|Date of Decision||16-Feb-2022|
|Date of Acceptance||19-Mar-2022|
|Date of Web Publication||15-Sep-2022|
Dr. Mansoor Ahmed Khan
Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, P. O. Box: 9515, Jeddah 21423
Source of Support: None, Conflict of Interest: None
CONTEXT: Tyrosine kinase inhibitors (TKIs) are the standard of care therapy for chronic myeloid leukemia (CML). The current disadvantages of lifelong treatment include adverse effects and financial burden.
AIMS: This study aimed to evaluate the outcomes of treatment-free remission (TFR) in CML patients.
SETTINGS AND DESIGN: A retrospective cohort study was conducted in our oncology center.
SUBJECTS AND METHODS: Patients ≥18 years old diagnosed with CML, received TKI and had a TFR trial to achieve TFR, with at least 6 months follow-up, and who received TKIs were included. Patients with a previous hematopoietic stem cell transplantation were excluded. The primary outcome was the proportion of patients with sustainable TFR at 6 months. The secondary outcomes were the proportion of patients with sustainable TFR at 12 months, the rate of regaining a major molecular response (MMR) after relapse, and the cost-saving impact. Descriptive statistics were used for the demographics and outcomes.
RESULTS: A total of 250 patients were screened for eligibility, 25 patients were enrolled. The median age was 54 years (interquartile range: 45.5–59), 60% were female. TFR was 92% at 6 months and 72% at 12 months. 100% of the patients regained MMR. The total number of TFR days were 17,024 which resulted in a direct cost saving of SR 7,205,601.9, based on Saudi FDA pricing.
CONCLUSIONS: The study indicated that the majority of the CML patients achieved 6 months TFR. This initiative has resulted in a significant cost saving. Future studies should characterize potential candidates for TKI discontinuation.
Keywords: Chroniac myeloid leukemia, molecular remission, treatment-free remission, tyrosine kinase inhibitors
|How to cite this article:|
Noor AM, Khan MA, Al-Thomali MM, Alnatsheh AH, Absi AA, Hakami FM, Alshamrani MA. Evaluation of tyrosine kinase inhibitor discontinuation initiative in patients with chronic myeloid leukemia at princess noorah oncology center. J Appl Hematol 2022;13:126-31
|How to cite this URL:|
Noor AM, Khan MA, Al-Thomali MM, Alnatsheh AH, Absi AA, Hakami FM, Alshamrani MA. Evaluation of tyrosine kinase inhibitor discontinuation initiative in patients with chronic myeloid leukemia at princess noorah oncology center. J Appl Hematol [serial online] 2022 [cited 2022 Oct 6];13:126-31. Available from: https://www.jahjournal.org/text.asp?2022/13/3/126/356088
| Introduction|| |
Chronic myeloid leukemia (CML) is a myeloproliferative disease that originates in hemopoietic stem cells due to a t(9;22) translocation, creating the Philadelphia (Ph) chromosome and BCR- ABL oncoprotein p210. The BCR-ABL chimeric protein is thought to play a central role in the pathogenesis of Ph chromosome-positive leukemia. The activity of the oncogenic proteins encoded by the BCR-ABL gene is specifically targeted by tyrosine kinase inhibitors (TKIs), which have become the standard therapy for Ph chromosome-positive CML according to international guidelines.
Treatment with TKIs can achieve durable cytogenetic and molecular remissions (MRs) and substantially improve the survival in the majority of CML patients. In addition, there is an expectation of curing the disease due to the high percentage of patients achieving deep molecular response., Until recently, the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines and the European LeukemiaNet guidelines for CML recommended the indefinite continuation of TKI treatment in all responding patients. Lifelong treatment causes several adverse events.,,, These include arterial hypertension, pleural effusion, and vascular events, which impair the quality of life of many patients,, in addition to the financial burden for patients, payers and health-care organizations.
TKI discontinuation attempt has a cost saving impact on institutional budget. A Lebanese study analyzed 162 patients diagnosed with CML receiving TKIs over a 4-year period. By using their national drug prices and by following the NCCN guidelines for TKI discontinuation, they concluded that the estimated total cost of CML treatment with treatment-free remission (TFR) over 4 years can be reduced by more than 7 million US dollars.
The NCCN guideline proposed criteria for TKI discontinuation to ensure the safety of the new initiative. The criteria include (1) age ≥18 years, (2) chronic phase CML with no prior history of accelerated or blast phase CML, (3) using approved TKI therapy for at least 3 years, (4) prior evidence of a quantifiable BCR-ABL1 transcript, (5) a stable molecular response (MR4; BCR-ABL1 ≤0.01% IS) for ≥2 years, as documented in at least four tests performed at least 3 months apart, (6) access to a reliable quantitative polymerase chain reaction (qPCR) test with a sensitivity to detect at least MR4.5 (BCR-ABL1 ≤0.0032% IS) and that provides results within 2 weeks, (7) monthly molecular monitoring for the first 6 months following discontinuation, 2 monthly during months 7–12, and 3 monthly thereafter (indefinitely) is recommended for patients who remain in MMR (MR3; BCR-ABL1 ≤0.1% IS), and (8) prompt resumption of TKI within 4 weeks of the loss of MMR with monthly molecular monitoring until MMR is re-established, then every 3 months subsequently for patients who have reinitiated TKI therapy after a loss of MMR. For patients who fail to achieve MMR after 3 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months.
The cessation of TKI treatment in eligible patients is an innovative and cost-effective strategy to optimize patient care outcomes. Several studies have shown that ~40% of patients in a stable deep molecular response (DMR) stay in TFR after discontinuing treatment.,,,, The majority of the patients who relapse after discontinuing TKI therapy (80%), do so within the first six months of treatment cessation. The molecular response was regained in almost all the patients when the same TKI was resumed.,, In general, following molecular relapse, patients remain responsive to TKI and regain molecular response. However, the definitions of molecular response varied over time. The current definitions distinguish multiple categories of MR through the detectable BCR-ABL transcripts and the individual test's sensitivity, which was not the case when the first discontinuation studies were initiated.,
There are many promising results from TKI discontinuation studies, encouraging TFR trials. This approach has been confirmed in the multicenter stopping imatinib (STIM) study which included one hundred chronic phase CML patients on first-line imatinib therapy. Almost half (43%) achieved TFR (95% confidence interval [CI], 33%–52%) at 6 months and 38% (95% CI, 29%–47%) at 60 months.
The ISAV study was a multicenter study, which confirmed the STIM results and included 112 patients with ≥2-year imatinib treatment and ≥18 months of undetectable transcripts in real-time (RT)-qPCR. The patients were followed for a median of 60 months. The study indicated a 47.7% TFR rate at 79 months and almost half (48%) of the patients had relapsed. The largest multicenter study is the European Stop Kinase Inhibitor (EURO-SKI) trial of the European LeukemiaNet. This study included 868 patients and was conducted in 61 centers in 11 countries. TFR were achieved in 61% (95% CI, 57%; 64%). The Japanese Dasatinib Discontinuation (DADI) study evaluated TFR after DADI, which was used as a second-line treatment. Over 44-month follow-up, the TFR rate was 49%, 48%, and 44.4% at 6, 12, and 36 months, respectively. All patients had a molecular relapse within the first 7 months of stopping dasatinib. Interestingly, all patients who had a molecular relapse regained a molecular response within 6 months after resuming TKI and the majority of the patients (n = 29) responded within 3 months.
However, there is no clear recommendation in international guidelines for TKI discontinuation. There are no studies published in the Middle East that have evaluated this new practice. Therefore, we aimed to conduct this study at our oncology center. We implemented the concept in our CML patient population 3 years ago. It is essential to evaluate the clinical efficacy in terms of TFR and cost-saving impact, which was also recommended by our Corporate Pharmacy and Therapeutic Committee.
Aim of the study
The evaluation of TKI discontinuation in CML patients with long-lasting and DMR, in terms of TFR and the cost impact.
The primary outcome was to identify the proportion of patients with a sustainable TFR at 6 months. TFR was defined as the time from TKI discontinuation to the date of TKI resumption. The TFR trial was initiated by the treating physician.
The secondary outcomes were to identify the proportion of patients with a sustainable TFR at 12 months, to assess the median time to molecular relapse, defined as the loss of a major molecular response (MMR) (BCR-ABL1 >0.1% on the International Scale (IS), to assess the rate of regaining MMR which is defined as BCR-ABL1 <0.1% on the International Scale after the TKI resumption, and to evaluate the cost saving impact of discontinuing TKI, which refers to the direct cost of the TKI treatment saved during the TFR period (days) using the Saudi FDA pricing of TKIs in Saudi Riyals (SAR).
| Subjects and Methods|| |
This was a retrospective cohort study conducted in our oncology center. The study was approved by the IRB office of King Abdullah International Medical Research Center on February 17, 2020, with a study number RJ19/176/J received through a memo reference number IRBC/0249/20. The patients were eligible for enrolment if they met the following criteria: adult patients (≥18 years) with a confirmed diagnosis of CML in the chronic or accelerated phase and who received imatinib, dasatinib or nilotinib treatment at the standard dose in the first-or second-line treatment, patients who discontinued TKI for TFR trial and had at least six months of follow-up in the hematology outpatient clinic. Patients with previous allogeneic hematopoietic stem cell transplantation were excluded.
The molecular laboratory records were used to determine the duration of a DMR before discontinuing TKI, the molecular status at the time of TFR, the molecular status at the time of resuming TKI, the best molecular response after resuming TKI, and the duration until the best response post-TKI resumption was achieved and the date of relapse.
The sampling technique was a convenient sampling of eligible patients, as described in the study participant section.
Definitions of molecular response and molecular relapse
Molecular monitoring was performed using the IS for BCR-ABL1 level in peripheral blood. The molecular responses are reported as a percentage of the ratio of BCR-ABL1 transcripts to those of a control gene. RT-qPCR is usually done on a peripheral blood sample, with a sensitivity of at least 4-log reduction from the standardized baseline. A MMR was defined as BCR-ABL1 IS transcripts of 0.1% or less (MR3). DMRs include MR4.0 (BCR-ABL1 ≤0.01%), MR4.5 (BCR-ABL1 ≤0.0032%), and MR5 (BCR-ABL1 ≤0.001%). A molecular relapse was defined as a 1-log increase in the BCR-ABL1 transcript levels with a loss of MMR.
| Results|| |
A total of 250 patients were screened for eligibility, and 25 patients were included in the study [Figure 1]. The median age of participants was 54 years (IQR; 45.5-59), with 60% female and 40% male. The median TKI treatment time was 8.46 years (IQR; 5.45–12.06) and all patients presented with the chronic phase at diagnosis. The median duration of a DMR before TKI discontinuation was 6.2 years (IQR; 4.5–7.9) [Table 1].
The majority (92%, n = 23) had a sustainable TFR at 6 months [Figure 2] and 72% (n = 18) achieved TFR at 12 months. A small proportion (16%, n = 4) was still in remission but had not completed the 12-month follow-up [Figure 3].
|Figure 2: Primary outcome (Patients with sustainable treatment free remission at 6 months)|
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|Figure 3: Secondary outcome (Patients with sustainable treatment free remission at 12 months)|
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Three patients (12%) had a molecular relapse after 28, 98, and 206 days of TKI discontinuation, and 100% regained MMR after resuming the same TKI. Two patients resumed TKI after losing the MMR and one patient resumed at MR3. The best molecular response after resuming TKI was MR5 in two patients after 5 and 14 months and MR4 after 7 months in the third patient.
Ten patients (40%) had achieved more than two years TFR and still responding, three of them have reached to three years of TFR [Figure 4].
|Figure 4: Treatment free remission for all included chronic myeloid leukemia patients|
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The total number of TFR days in the study was 17,024 days which resulted in a direct cost saving of SR 7,205,601.9 using Saudi FDA listed prices for imatinib, dasatinib and nilotinib. This is a significant cost saving on the stretched budget of our organization [Table 2].
| Discussion|| |
The management of a chronic disease requires long-term or life-long therapy, which may have significant consequences in terms of adverse effects and financial burden. Further, young women may be interested in discontinuation of therapy for family planning purposes.,, The depth and stability of long-term responses to imatinib led to the investigation of treatment discontinuation. The ability to maintain undetectable minimal residual disease or detectable at a stable low level after TKI discontinuation has been termed TFR.
Many prospective and retrospective studies in the last 10 years have proven the safety and efficacy of TKI discontinuation in selected CML patients, especially patients who achieved a DMR with TKI. This has moved prime-time into clinical practice although open questions remain in terms of understanding the disease biology that leads to successful TKI cessation in some patients but not in others. The majority (80%) of the patients who relapse after discontinuing TKI therapy do so within the first 6 months of treatment cessation. The molecular response is regained in almost all the patients when the same TKI is resumed.,,
Based on the encouraging evidence supporting the discontinuation of TKI in selected CML patients, our adult Hematology and Clinical Pharmacy Department initiated this practice a few years ago and TFRs were offered to CML patients based on the criteria listed in the NCCN guidelines for TKI discontinuation in CML patients.
The findings of the current study have been impressive and the TFR results have been unprecedented in comparison to other published studies. The study demonstrated TFR rates of 92% at 6 months and 72% at 12 months although four patients (16%) were still in remission without completing the 12-month follow-up. The TFR rates were maintained at 12 months, which was higher than what was reported in previous trials, including STIM 2010,, DOMEST, EURO-SKI, and JALSG-STIM213. For instance, the STIM trial,, a prospective, multicenter, nonrandomized trial, investigated imatinib discontinuation in one hundred patients in chronic phase CML after 2 years of treatment and sustained CMR for 2 years, almost half of the patients (43%) achieved TFR at 6 months (95% CI, 33% to 52%) and (41%) achieved TFR at 12 months. The majority of the patients who relapsed (95%), did so within six months of TKI discontinuation. Around 96% of the patients who lost the molecular response regained MMR in a median time of 4 months after treatment resumption with the same TKI, which is supported by our findings.
The DOMSET trial which assessed the safety and efficacy of imatinib discontinuation included patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years. The median duration of imatinib therapy was around 8 years. The study showed a lower TFR rate in comparison to the current study findings, with a 6-month TFR rate of 69.6% and a 12-month TFR rate of 68.6%. In the EURO-SKI trial, the largest prospective, nonrandomized trial investigated TKI discontinuation after at least 3 years, mainly imatinib as first line in 785 CML patients, and had a confirmed DMR for at least 1 year. TFR were achieved in 61% (95% CI, 57%; 64%) at 6 months and 50% (46–54) at 24 months. The JALSG-STIM213 trial also investigated imatinib discontinuation after ≥3 years treatment and sustained DMR for ≥2 years, reported a 12-month TFR rate of 67.6%.
One of the reasons for the higher TFR rates in our study at 6 months could be the longer period of taking TKI, as well as the longer period of sustained DMR in comparison to literature. Our patients were on DMR for at least 4 years, before TKI discontinuation was initiated.
Every study has limitations, our study is not a randomized study. However, it provides a real-life experience, outside a clinical trial, which has restricted eligibility criteria. The sample size was small; however, it is considered a novel initiative and new practice. TFR results have encouraged us to offer TKI discontinuation to more CML patients according to the approved criteria for TKI discontinuation.
The strengths of the study include being the first study in the Middle East that evaluated TFR and confirmed the positive impact of TKI discontinuation in the Saudi population.
Three TKIs namely, imatinib, dasatinib, and nilotinib are on the list of the most expensive oncology medication used at Princess Noorah Oncology Center for the last few years. However, the TKI discontinuation initiative appears to be an attractive cost-saving strategy, in addition to the psychological well-being of the patients. We suggest evaluating all the CML patients in our hospital and other hospitals of our corporate organization for TKI discontinuation, as per the NCCN guideline criteria to further enhance the cost-saving impact.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]