Imatinib Discontinuation Research Articles

Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial

The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

Discontinuation of imatinib in patients with oligometastatic gastrointestinal stromal tumour who are in complete radiological remission: a prospective multicentre phase II study.

Metastatic gastrointestinal stromal tumour (GIST) is considered incurable, and life-long treatment with tyrosine kinase inhibitors is recommended. We investigated whether selected patients with metastatic GIST may remain in durable remission despite imatinib discontinuation. In this 1-group, prospective, multicentre phase II trial selected patients with oligometastatic (≤3 metastases) GIST discontinued imatinib treatment. Eligible patients had been treated with imatinib >5 years without progression and had no radiologically detectable metastases after metastasectomy, radiofrequency ablation (RFA) or complete response to imatinib. The primary endpoint was progression-free survival (PFS) 3-years after stopping imatinib. Overall survival (OS) and quality of life (QoL) were secondary endpoints. The trial closed prematurely due to slow accrual. Between January 5, 2017, and June 5, 2019, 13 patients were enrolled, of whom 12 discontinued imatinib. The median follow-up time was 55 months (range, 36 to 69) after study entry. Five (42%) of the 12 eligible patients remained progression free, and seven (58%) progressed with a median time to progression 10 months. Median PFS was 23 months and the estimated 3-year PFS 41%. Six of the seven patients who progressed restarted imatinib, and all six responded. Three-year OS was 100%, and all patients were alive at the time of the study analysis. QoL measured 5 and 11 months after discontinuation of imatinib demonstrated improvement compared to the baseline. A substantial proportion of selected patients with oligometastatic GIST treated with imatinib and metastasis surgery/RFA may remain disease-free for ≥3 years with improved QoL after stopping of imatinib.

High Level of CD8+PD-1+ Cells in Patients with Chronic Myeloid Leukemia Who Experienced Loss of MMR after Imatinib Discontinuation.

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib.

Long-term Results of Imatinib Discontinuation in Patients with Chronic Phase Chronic Myeloid Leukemia: National Multicenter Prospective Study.

The discovery of imatinib is a milestone for chronic myeloid leukemia (CML) (1). As life expectancy in CML patients has approached that of the general population (2), research has shifted towards improving quality of life and economic considerations. After 2010, it has been shown that some patients could maintain molecular response even after discontinuing imatinib (3). This national multicenter prospective cohort study aimed to observe the long-term consequences of discontinuing imatinib therapy in adult chronic phase CML patients. A total of 41 patients were included. The median follow-up time after imatinib discontinuation was 48 months (minimum-maximum 6-81 months). The rate of molecular relapse-free survival (MRFS) at 48 months was 33,2% (CI:48.2-18.2). Twenty-seven of 41 patients lost their major molecular response MMR, treatment was started again, and the molecular response was re-achieved with imatinib in all patients. There was no significant relationship between molecular relapse and clinical factors like duration of treatment or molecular response status. Discontinuing imatinib resulted in approximately 4,392,000 Turkish Liras (TRY) or 245,150 US dollars (USD) in savings. In conclusion, imatinib discontinuation with close molecular monitoring is a safe option and provides important national economic benefits and enhanced quality of life. This approach should be considered for all eligible patients. This is the first tyrosine kinase inhibitor discontinuation study from Turkey.

Higher incidence of delayed methotrexate clearance in pediatric acute lymphoblastic leukemia patients treated with imatinib

BackgroundPediatric patients with Philadelphia chromosome positive (Ph+) or ABL-class fusion positive acute lymphoblastic leukemia (ALL) are currently treated with the tyrosine kinase inhibitor (TKI) imatinib added to a chemotherapy backbone that also contains several courses of high-dose methotrexate (HDMTX). A limited number of case studies suggested delayed MTX clearance in patients concomitantly using HDMTX and imatinib. MethodsMTX clearance and serum creatinine in 24 newly diagnosed Ph+/ABL-class fusion positive pediatric ALL patients treated with imatinib (imatinib group) were compared with 281 randomly selected age-matched Ph-negative pediatric ALL patients treated without TKI (control group), receiving in total 61 and 897 HDMTX courses, respectively. ResultsMild to severe delayed MTX clearance (MTX level at T48 hours>0.4 µM) was more frequently found in the imatinib group than in the control group in all courses (55.7% vs 41.1% p = 0.036). After the first HDMTX course, 12.5% (n = 3) of the imatinib group presented with a severe delayed MTX clearance (T48 > 5 µM) versus 2.3% in the control group (p = 0.039). In two (8.3%) of these patients in the imatinib group, this was accompanied by increased creatinine, therefore meeting the criteria for Delayed MTX Elimination (DME). In the control group 12/281 (4.3%) patients presented with DME. Glucarpidase was administered in 2 (8.3%) vs 4 (1.4%) patients in the imatinib group and control group, respectively. ConclusionImatinib increased the risk of delayed MTX clearance in newly diagnosed pediatric Ph+ chromosome or ABL-class fusion positive ALL patients. We therefore recommend stringent supportive care measures and for patients with severe delayed MTX clearance resulting in severe toxicities temporary discontinuation of imatinib or a lower dose of MTX during the next HDMTX courses.

Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.

Multiple studies have reported a significant treatment-free remission (TFR) rate of 50%-60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re-initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re-therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post-imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach.

Peripheral lymphocyte subsets as predicting factors for molecular recurrence after imatinib discontinuation in a phase 2 imatinib discontinuation trial in patients with chronic myeloid leukemia

IntroductionTreatment-free remission (TFR) is successful in half of the patients with chronic myeloid leukemia who discontinue Imatinib (IM) after sustained molecular response. MethodsIn a prospective trial, we used pioglitazone for 3 months before stopping IM in 30 patients. Percentages of peripheral blood lymphocyte subsets were assessed before and after treatment. The relation of these data with duration of IM treatment and TRF were examined. ResultsThe median time of IM treatment was 117.6 months. After discontinuation, 11 patients had molecular recurrence after 5.2 months (2.4 – 30). The observation time for those remaining in TFR was 46 (26 – 56) months. The independent factors for the maintenance of TFR were the duration of IM treatment and the percentage of double-positive T cells at IM stop. ConclusionA longer treatment with imatinib was associated with a longer TFR after discontinuation. Pioglitazone could act as an immunomodulator, increasing DP T cells which may contribute to prevent relapse.

Inclusion body myositis triggerred with long-term imatinib use.

Imatinib is an orally administered tyrosine kinase inhibitor with wide clinical use in different indications from solid tumors to hematologic malignancies. Inclusion body myositis (IBM) is an acquired myopathy of both inflammatory and degenerative nature. We present an 81 years old male with a history of gastrointestinal stromal tumor (GIST) operated 8 years ago and was evaluated for the progressive loss of weight and muscle strength leading to total immobilization in 6 months. He was under imatinib for 8 years despite the remission of GIST. Physical examination disclosed diffuse loss of muscle strength, most prominently involvement of distal upper and proximal lower extremity in an asymmetrical pattern with normal serum creatinine kinase level (CK). Further investigations including bilateral thigh MRI, electromyography (EMG), and PET/CT suggested myositis and degenerative myopathy and ruled out any malignancy. Quadriceps femoris biopsy proved the diagnosis of IBM and no trigger except for imatinib was displayed. Clinical improvement in terms of weight loss and muscle weakness was achieved after the discontinuation of imatinib. This is the first case of IBM associated with prolonged use of imatinib not reported in the literature so far. Since imatinib is widely used in different conditions, it is important to be aware of even its rare adverse effects. Poor response of IBM to conventional immunosuppressive agents enhances the value of etiology identification to relieve symptoms in addition to supportive care.

Treatment-free remission after discontinuation of imatinib, dasatinib, and nilotinib in patients with chronic myeloid leukemia

Patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy are expected to have long-term survival outcomes comparable to those of the general population. Many clinical trials have confirmed that some patients sustain molecular responses without continuing TKI therapy. Treatment-free remission (TFR) is a new goal in treating chronic CML. The safety and outcome of TFR were studied in clinical trials after discontinuing imatinib or the second-generation TKIs dasatinib or nilotinib. TFR was safe in approximately 50% of patients who achieved a deep molecular response to TKI therapy. Patients who relapsed after discontinuing TKI responded immediately to the reintroduction of TKI. The mechanism by which TFR increases the success rate still needs to be understood. The hypothesis that the modulation of immune function and targeting of leukemic stem cells could improve the TFR is under investigation. Despite the remaining questions, the TFR has become a routine consideration for clinicians in the practice of molecular remission in patients with CML.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Treatment free remission in pediatric chronic myeloid leukemia

BackgroundThe aim was to evaluate the impact of discontinuation of imatinib in children in chronic phase of chronic myeloid leukemia (CML) and assess treatment free remission (TFR). Patients and methods: We performed a retrospective study in children diagnosed with CML chronic phase up to 18 years of age, who were on imatinib for 5 years and had consistent BCR:ABL1 negative/undetectable transcripts through RT-PCR. Complete blood counts were monitored monthly and BCR:ABL1 transcripts by RT-PCR monitored 3 months. Results: Among the 14 patients who continued to remain PCR negative, we attempted discontinuing imatinib in eleven children as per the above-mentioned criteria. Eight (72%) continued to be in remission and did not require imatinib to be restarted. Among the remaining three patients, one child was noted to have increasing basophilia in the differential counts and was hence restarted on imatinib. Two other patients demonstrated recurrence of BCR:ABL1 transcript copy numbers six months after stopping TKI, following which imatinib was restarted. All three patients had documented major molecular response within three months of therapy. The median duration of TFR was 18 months in our cohort (range: 3 months–5 years). Among patients who continued to be off imatinib, TKI withdrawal symptoms were documented in 4 (36%) patients. Conclusions: Treatment free remission was achieved in 8/11 (72%) children after discontinuation of imatinib, and re-introduction of imatinib resulted in major molecular response in those with recurrence. Monitoring of BCR:ABL1 transcripts through RT PCR is essential.

Financial Impact of Imatinib Discontinuation in Brazil - a Real World Evidence Pharmacoeconomic Study in Chronic Myeloid Leukemia of a Private Institution

Introduction Recent studies showed that tyrosine kinase inhibitors (TKI) treatment could be safely discontinued in a selected group of chronic phase (CP) chronic myeloid leukemia (CML) patients that achieved deep molecular response (DMR), making treatment-free remission (TFR) a new goal of therapy. The discontinuation treatment in patients with sustained molecular response to MR4 or MR4.5, a practice that has been performed and consolidated since 2011 in other countries, is not feasible in Brazil outside clinical trials because of the lack of coverage for performing RQ-PCR as recommended by the international guidelines. For all these aspects, it seemed essential to us to analyze the financial impact of TKI discontinuation, following strict monitoring criteria, and perform a projection of economic costs in a population of CML patients treated in first-line with imatinib eligible for discontinuation. Aims: To demonstrate the feasibility of coverage of Q-PCR to perform discontinuation of imatinib treatment on eligible patients [ treatment free-response (TFR)] in Brazil based on the financial impact Material and Methods From 2020 -2021, 26 eligible patients from a single private institution in Brazil were invited to participate in a single-arm trial of Imatinib discontinuation (DIP). Inclusion criteria: age > 18 years, chronic phase, minimum of 04 years of Imatinib therapy, a deep molecular response sustained > or = 02 years (confirmed by 04 tests in the last two years, defined MR4.0 or MR 4.5 and a confirmatory exam at the moment of the screening). After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year, and every three months after the third year. Criteria for Imatinib re-initiation were the same of the Euro-Ski trial. Considering that US$ 1.00 are R$ 5.3 ( Brazilian currency- March /2022 ) for Branded Imatinib - 400 mg/d, the monthly cost has been estimated at R$ 16,933.90 or US$ 3,95.07 and the generic imatinib- 400mg/d monthly R$ 13,048.90 or US$ 2,462.05 ( CEMED- March/2022). The unitary value for the Q-PCR exam has been estimated, with a large price range at R$ 1,311.25 (R$790.00 to R$ 2,159.00) or US$ 247.40. Results Of 26 patients, 20 consent to discontinuation of imatinib. Six patients declined despite information because of their insecurity about TFR. Twelve patients (60%) presented MR4. The median age was 52.3, and 13 (65%) were female. Median time diagnosis to discontinuation of imatinib 8.5 (4.6-15.5) years. Twelve (60%) patients sustained TFR. . In this interim analysis, the median time of follow-up was 14.5 (2.7-18.8) months. During the follow-up, 244 RQ-PCR were performed. The cumulative time without treatment was 224.5 months. The costs with Q-PCR were R$ 319,945.00 or US$ 60,366.98 (244 exams during follow-up (median time 14,4 months). The average time of months without treatment was 224.5 months. The cost of treatment without discontinuation would be R$ 4,131,871.60 or US$ 779,598.41 (Branded Imatinib) or R$ 2,929,478.05 or US$ 552,731.70 (imatinib copies). The saving on median time of follow-up (14.4 months ) were R$ 3,811,926.60 or US$ 719,231.43 (Branded Imatinib) or R$ 2,609,533.05 or US$ 492,364.72 (imatinib copies). Discussion: Considering the methodology of Cost-Utility, the saving resulting from the discontinuation of treatment for 20 patients for 14.4 months despite the loss of MR of 40 % of patients were R$ 3,811,926.60 or US$ 719,231.43 (Branded Imatinib) or R$ 2,609,533.05 or US$ 492,364.72 (imatinib copies). The results show that if Q-PCR tests were available in clinical practice, within pre-established protocols, there would be equalization and adequacy with the international monitoring guidelines, and discontinuation protocols could be feasible in clinical practice. Conclusion: The possibility of discontinuation would have a huge financial impact on the Brazilian Health System, resulting in the economic viability of treating hundreds of patients and performing thousands of Q-PCR exams, creating a rational and balanced model of clinical efficacy coupled with basic sustainability premises of modern oncology.

Five-Year Follow-up of the Phase I/II Discontinuation Trial of Imatinib after Pioglitazone (EDI-PIO) in Chronic Myeloid Leukemia Patients in Deep Molecular Response

Treatment-free remission (TFR) is successful in approximately 40-60% of CML patients who achieve a stable and deep molecular response. Relapses may occur due to the persistence of quiescent leukemic stem cells (LSC). Pioglitazone, a drug used for diabetes, is a PPAR gamma agonist and reduces STAT5 activity, and its downstream targets HIF2α and CITED2, key guardians of the quiescent LSC. Residual LSC can be gradually purged from bone marrow niches by pioglitazone. Objectives: to evaluate the efficacy and safety of pioglitazone used with imatinib before treatment discontinuation. Methods: EDI-PIO (from the Portuguese Estudo de Descontinuação de Imatinibe após Pioglitazona) is a prospective, single arm, phase I/II discontinuation trial. Inclusion criteria: CML in chronic phase, treated with IM for at least 3 years, with MR4.5 reported by the International Scale (IS) for 2 years. Patients received pioglitazone 30 mg/day orally for three months before IM discontinuation. After discontinuation, BCR-ABL levels were measured by real-time quantitative PCR monthly for 12 months, every two months in the second year, and then every three months. IM was re-initiated at molecular relapse (single sample with a value of >0.1% or two consecutive samples >0.01%). TFR was calculated from IM discontinuation until molecular relapse, progression, or death to causes related to CML. Overall survival (OS) was calculated from IM discontinuation until the last seen or death date by any cause. This trial is registered with Clinicaltrials.gov, NCT02852486. Results: Between Jun/2016 and Jan/2019, we evaluated 32 CML patients, with a median age of 54 years (29-77), treated with imatinib for a median time of 9.5 years (3-16). The median duration of MR4 and MR4.5 was 106 and 93 months, respectively. The cut-off date for this analysis was July 1st, 2022. One patient left the trial before imatinib discontinuation and was not analyzed for TFR. There were no grade 3 or 4 adverse events related to pioglitazone. The median follow-up of the 31 patients that discontinued IM was 61 months (37-69). As previously reported, 15/31(48%) patients presented symptoms related to withdrawal syndrome. Twelve patients presented molecular relapse after a median time of 5 months (2-30). Nine relapses in the first six months and three at 7, 13, and 30 months after stopping imatinib. All relapsed patients re-achieved MMR in a median time of 3 months (1.8-4.1). One patient developed an anal canal adenocarcinoma in the third year after discontinuation and was treated with surgery and chemotherapy. TFR was 71%, 67%, 61% and 61% at 6,12, 30 and 60 months (Figure 1A), respectively. 60-month OS was 95% (CI 95%: 85-100%)(Figure 1B). There were 5 cases of COVID-19 among the 19 patients in TFR (26%) and two suspects. Four cases were mild, and one patient in MR4.5 died due to severe COVID-19. Sokal score and MR4.5 duration were significant factors for prolonged TFR (P=0.032 and 0.012, respectively). Conclusions: the combination of pioglitazone and IM was feasible and safe, with TFR rates consistent with previous discontinuation trials. The 5-year long-term follow-up demonstrated durable and stable molecular responses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment-Free Response in Chronic Myeloid Leukemia Using Brazilian Imatinib Copies As First Line - Results from Two Prospective Clinical Trials

Introduction: Several trials have demonstrated the feasibility of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients with a deep molecular response, but little data is available about the results using imatinib copies. Brazil has been using imatinib copies as a first-line treatment since 2013. Aim: To report the results of two Brazilian imatinib copies trials and to evaluate factors impacting treatment-free remission (TFR) and treatment-free survival (TFS) after imatinib discontinuation. Methods: From Dec-2016 until Oct-2018 (USP trial, NCT03239886) and from Oct-2020 until Apr-2021(Hemomed Trial- DIP), 51 eligible patients were included to participate in two trials of imatinib discontinuation. Inclusion criteria: age > 18 years, chronic phase, minimum of three years (USP trial) and four years (DIP) of imatinib copies therapy, a deep molecular response, defined as MR4.0 or MR4.5 sustained for more than 2 years, and a confirmatory test at the moment of the screening. Atypical transcripts were excluded. After discontinuation, patients on the USP trial were monitored by Q-PCR monthly for the first 6 months and bimonthly after 6 months for the first year and quarterly afterwards. Patients in DIP monitoring were monthly for the first year and every 2 months in the second year. Minimal criteria for IM re-initiation was loss of major molecular response (MMR) confirmed by two exams. Results: Median age was 53 years at the time of discontinuation. 58% male (USP) and 65% female (DIP). Imatinib´s therapy was 9.9 years (3-15.5 y). 52.9% had MR4.5 at the screening. TFS at 6 months was 78% (95 Cl 67-90), 12 months 66% (95 Cl 54-80) and at 24 months 54% (95 Cl 42-71). TFS by center at 12 months were 64.5 % (USP) and 67% (DIP). TFS according to previous molecular response after 24 months of follow-up (MR4 vs. MR4.5) (p =0,086). MMR recovery was present in 100% with a median time of 3.5 months. Four patients are still on TFR because the double testing of MMR loss was not confirmed. Conclusion: These two trials demonstrated the feasibility and safety of imatinib discontinuation, even using Brazilian copies, and the results were similar to that presented in another trial. The confirmatory exam to establish the loss of TFR was useful and safe. However, the results no suggest a benefit on monthly Q-PCR after six months of follow-up. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment- Free Remission in Chronic Myeloid Leukemia -Experience of a Single Brazilian Private Institution Using Imatinib Copies

Introduction: In addition to the best possible overall survival, discontinuation of the tyrosine kinase -inhibitor (TKI) treatment [treatment free response (TFR)] without observing a recurrence of the disease has become a standard part of chronic myeloid leukemia (CML) care. Evidence of several studies suggest that patients who have achieved a sustained stable deep molecular response (DMR) as MR4 and MR4.5 can be safely discontinued with close monitoring without relapse, despite BCR/ABL1 DNA remaining detectable. In Brazil, CML patients have received almost exclusively Imatinib as first-line treatment and since 2013, only generics and copies of imatinib mesylate have been used in first-line throughout the whole Public Health System and in several institutions within the private system. However, in both scenarios there is a limit coverage of PCR exams/ year which allows for adequate monitoring but it is not sufficient for the implementation of TFR safely in eligible patients Aims: To report a Brazilian single institution Imatinib discontinuation trial and to evaluate factors impacting treatment -free response (TFR) and treatment free survival (TFS) Methods: From 2020 -2021 , 26 eligible patients were invited to participate in a single arm trial of Imatinib discontinuation (DIP). Inclusion criteria: age > 18 years, chronic phase, minimum of 04 years of Imatinib therapy, deep molecular response sustained > or = 02 years (confirmed by 04 tests in the last two years, defined MR4.0 or MR 4.5 and a confirmatory exam at the moment of the screening). Atypical transcripts were excluded. After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year and every three months since the third year. Criteria for Imatinib re-initiation: loss of MMR confirmed by two exams, loss of cytogenetic response, loss of hematologic response, disease progression. TFR was calculated from the date of discontinuation until first event: loss of MMR, Imatinib reintroduction, death any cause or last follow up. TFS was calculated from the date of imatinib discontinuation until reintroduction or last follow- up (censoring deaths not related to CML). The costs of exams were provided by own founds of our institution. Results: From 26 patients, 20 patients agreed to consent inform to discontinuation of imatinib. 06 patients declined despite information because their insecurity about TFR. Twelve patients (60%) presented MR4 . Median age was 52.3 years old and 13 (65%) were female. Median time diagnosis to discontinuation of imatinib 8.04(4.6-15.5) years. Twelve (60%) patients sustained TFR. Seven patients of twelve had presented MR 4 and five had MR 4.5 in the screening, respectively . (p=0,85) .It means 58,3% of the total of patients with MR 4 and 62,5% with MR 4.5 . In this interim analysis the median time of follow up was 14.5 (2.7-18.8) months. One patient died due to COVID19 with major molecular response (MMR). Eight (40%) lost MMR and imatinib was restarted. In this group the median time until MMR loss was 7.24 (2.1-13.8) months. At this moment, 07 patients (87,5 %) recovered MMR . In addition , in this group 06 patients (75%) achieved the same level of MR with reintroduction of imatinib with median 5.2 (3.7-6.3) months. Regarding adherence, 4 (20%) had some absences in monthly medical consultations and 1(5%) missed follow-up. Fifteen tests (6.14%) were performed to confirm MR loss, however only in 8 tests (53.3%) were confirmed. In fact, 04 patients (33,33%) still in TFR because of the double confirmatory test. There was no transformation to advanced phases. Gender, age at de diagnosis , age at discontinuation, Sokal , BCR-ABL trasncripts type , duration of Imatinib therapy , duration of MR 4.0 or MR4.5 did not affect TFR. Withdrawal syndrome occurred in 05 patients (25%) ; 04 patients with grade 1 and 01 patient with grade 2, had been used corticosteroid for few days. Conclusions: Despite the small number of patients included and short time of follow-up, the preliminary results of this trial demonstrated the feasibility and safety of Imatinib discontinuation , even using Brazilian copies, and the results were similar of that presented in another trials . The confirmatory exam to establish the loss of TFR was useful and safe. Adhesion of a discontinuation is one of the most important keys of the success of TFR.

Risk Factor Analysis for Second Treatment-Free Remission Failure from the Canadian TKI Discontinuation (TRAD) Trial in CML Patients: Treatment-Free Remission Accomplished By Dasatinib

Background The Canadian TKI discontinuation (TRAD) trial (NCT02268370) has evaluated whether Dasatinib (DA) rechallenge can sustain a second treatment-free remission (TFR2) after failure of Imatinib (IM) discontinuation (DISC) for the first TFR (TFR1) attempt. We previously reported that: 1) The 12-month molecular relapse-free survival (mRFS) rate for TFR1 is 58.0%; 2) Re-challenge with DA following TFR1 failure after IM DISC restores deep molecular response (MR) quickly; 3) 12 months DA rechallenge does not significantly improve TFR2 rate (EHA 2022). The clinical risk factors associated with TRF2 failure are evaluated in this study. Patients and Methods This prospective study (BMS CA180-543, NCT#02268370) had 3 phases: 1) IM discontinuation for TFR1, 2) DA rechallenge, and 3) DA discontinuation for TFR2. Key inclusion criteria included: 1) CML in chronic phase, 2) minimum duration of IM therapy 3 years, 3) minimum duration of MR4.5 or deeper over 2 years. Molecular relapse was defined as an increase BCR::ABL qPCR >MR4 on 2 consecutive occasions, or a single increase in BCR::ABL qPCR >MR3. DA treatment was started at 100mg daily after molecular relapse was confirmed, and continued for at least 12 months after achieving ≥MR4 until TFR2 is attempted. Molecular relapse-free survival (RFS) after DA discontinuation was calculated and analyzed according to the risk factors. Results With a median follow-up duration of 27.5 months (range 1.8-51), in the TFR2 phase, 35 pts stopped DA for a TFR2. Only 3 of 35 pts (8.6%), maintained the MR at last follow-up, the remaining 32 lost the MR within a median 3.65 months. The actuarial mRFS rate at 6 and 12 months was 22.9% (95% CI, 10.8-37.6%) and 10.0% (2.7-23.1%). Potential risk factors for TFR2 from three different phases were evaluated, and 5 were found to be associated with TFR2 failure in univariate analysis (table 1): 1. In the DA rechallenge phase, failure to achieve MMR in less than 1 month with DA rechallenge increased the risk of TFR2 failure, in comparison to those who achieved MMR in less than a month (HR 4.656, p=0.0002). 2. Prior to DA DISC phase, any detectable BCR::ABL1 qPCR level between MR4 to MR5.4 showed an increased risk of TFR2 failure, compared to undetectable BCR::ABL1 qPCR level below MR5.5 (HR 4.04, p=0.0001). 3. Among the variables during the IM DISC phase: 4. Molecular relapse pattern: in comparison to the loss of MR4 only, those who lost MMR had an increased risk of TFR2 failure (HR 4.163, p= 0.001). 5. Time to loss of MR within 2.8 months after IM DISC increased the risk of TFR2 failure, in comparison who lost MR beyond 2.8 months (HR 4.717, p=0.0002). 6. Shorter doubling time (DT) at 2 months below 12.75 days and above 0 increased the risk of TFR2 failure, compared to DT at 2 months above 12.75 days or below 0 (HR 654, p=0.002) Multivariate analysis was performed to identify independent risk factors, identifying 3 clinical factors predictive of TFR2 failure: 1) Failure to achieve MMR in less than 1 month following DA rechallenge (p=0.007, HR 9.542 [1.819-50]); 2) DT below 12.75 days at 2 months after IM DISC (p=0.015, HR 4.368 [1.334-14.30]); and 3) any detectable BCR::ABL1 transcript level between MR4 and MR5.4 before DA DISC (p=0.047, HR 2.759 [1.014-7.513]). A risk score model was generated incorporating these 3 clinical risk factors. A score of 1 was assigned to each one of these risk factors. The group with a score of 0 vs 1-3 was labeled as low vs high-risk, respectively. The low-risk group (n=7) showed 85.7% and 34.3% of TFR2 rate at 6 and 12 months, while the high-risk group (n=24) showed 7.4% and 3.7% of TFR2 rate at 6 and 12 months, (p=0.0003; HR 6.518 [2.219-19.95] for high-risk group vs low risk; Figure 1). Conclusion As we have previously reported, DA treatment rarely achieves a sustained TFR2 after failing the first IM DISC attempt. However, our current result suggests that TFR2 attempt can be successful in a selected group of patients if: 1) Rapid reduction of initial molecular kinetics is achieved within 1 month of DA rechallenge, 2) an undetectable BCR::ABL1 qPCR level is reached before TFR2 attempt 3) longer doubling time at 2 months after IM DISC is noted. The proposed risk model can be used as a predictive tool for TFR2 failure. Further studies to improve TFR2 rate should investigate the addition of new therapies and consider the use of innovative tools with higher precision and sensitivity to quantify the MR. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

FINANCIAL IMPACT OF IMATINIB DISCONTINUATION IN BRAZIL – A PHARMACOECONOMIC STUDY IN CHRONIC MYELOID LEUKEMIA OF A PRIVATE INSTITUTION

Recent studies showed that tyrosine kinase inhibitors (TKI) treatment could be safely discontinued in a selected group of chronic phase (CP) chronic myeloid leukemia (CML) patients that achieved deep molecular response (DMR), making treatment-free remission (TFR) a new goal of therapy. The discontinuation of treatment in patients with sustained molecular response to MR4 or MR4.5, a practice that has been performed in other countries is not feasible in Brazil outside clinical trials because of the lack of coverage for performing RQ-PCR as recommended by the international guidelines. For all these aspects, it seemed essential to us to analyze the financial impact of TKI discontinuation, following strict monitoring criteria, and perform a projection of economic costs in a population of CML patients treated in first-line with imatinib eligible for discontinuation. To demonstrate the feasibility of coverage of Q-PCR to perform discontinuation of imatinib treatment on eligible patients [ treatment free-response (TFR)] in Brazil based on the financial impact. From 2020 -2021, 20 eligible patients from a single private institution in Brazil were invited to participate in a single-arm trial of Imatinib discontinuation (DIP). After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year, and every three months after the third year. Criteria for Imatinib re-initiation were the same of the Euro-Ski trial. Considering that US$ 1.00 are R$ 5.3 (Brazilian currency- March /2022) for Branded Imatinib – 400 mg/d, the monthly cost has been estimated at R$ 16,933.90 or US$ 3,95.07 and the generic imatinib- 400mg/d monthly R$ 13,048.90 or US$ 2,462.05 (CEMED- March/2022). The unitary value for the Q-PCR exam has been estimated, with a large price range at R$ 1,311.25 (R$790.00 to R$ 2,159.00) or US$ 247.40. Of 26 patients, 20 consent to discontinuation of imatinib. Twelve patients (60%) presented MR4. Median time diagnosis to discontinuation of imatinib 8.5 (4.6-15.5) years. Twelve (60%) patients sustained TFR. During the follow-up, 244 RQ-PCR were performed. The cumulative time without treatment was 224.5 months. The costs with Q-PCR were R$ 319,945.00 or US$ 60,366.98 (244 exams during follow-up (median time 14,4 months). The average time of months without treatment was 224.5 months. The cost of treatment without discontinuation would be R$ 4,131,871.60 or US$ 779,598.41 (Branded Imatinib) or R$ 2,929,478.05 or US$ 552,731.70 (imatinib copies). The saving on median time of follow-up (14.4 months) were R$ 3,811,926.60 or US$ 719,231.43 (Branded Imatinib) or R$ 2,609,533.05 or US$ 492,364.72 (imatinib copies). Considering the methodology of Cost-Utility, the saving resulting from the discontinuation of treatment for 20 patients for 14.4 months despite the loss of MR of 40 % of patients were R$ 3,811,926.60 or US$ 719,231.43 (Branded Imatinib) or R$ 2,609,533.05 or US$ 492,364.72 (imatinib copies). The results show that if Q-PCR tests were available in clinical practice, within pre-established protocols, there would be equalization and adequacy with the international monitoring guidelines, and discontinuation protocols could be feasible in clinical practice. The possibility of discontinuation would have a huge financial impact on the Brazilian Health System, resulting in the economic viability of treating hundreds of patients and performing thousands of Q-PCR exams, creating a rational and balanced model of clinical efficacy coupled with basic sustainability premises of modern oncology.

TREATMENT- FREE REMISSION IN CHRONIC MYELOID LEUKEMIA -EXPERIENCE OF A SINGLE BRAZILIAN PRIVATE INSTITUTION USING IMATINIB COPIE

Evidence of several studies suggest that patients who have achieved a sustained stable deep molecular response (DMR) as MR4 and MR4.5 can be safely discontinued with close monitoring without relapse, despite BCR/ABL1 DNA remaining detectable. In Brazil, CML patients have received almost exclusively Imatinib as first-line treatment. However, in both scenarios there is a limit coverage of PCR exams/ year which allows for adequate monitoring but it is not sufficient for the implementation of TFR safely in eligible patients. To report a Brazilian single institution Imatinib discontinuation trial and to evaluate factors impacting treatment -free response (TFR) and treatment free survival (TFS) provided by own founds. From 2020 -2021, 26 eligible patients were invited to participate in a single arm trial of Imatinib discontinuation (DIP). Inclusion criteria: age > 18 years, chronic phase, minimum of 04 years of Imatinib therapy, deep molecular response sustained > or = 02 years (confirmed by 04 tests in the last two years, defined MR4.0 or MR 4.5 and a confirmatory exam at the moment of the screening). Atypical transcripts were excluded. After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year and every three months since the third year. Criteria for Imatinib re-initiation: loss of MMR confirmed by two exams, loss of cytogenetic response, loss of hematologic response, disease progression. TFR was calculated from the date of discontinuation until first event: loss of MMR, Imatinib reintroduction, death any cause or last follow up. TFS was calculated from the date of imatinib discontinuation until reintroduction or last follow- up (censoring deaths not related to CML). The costs of exams were provided by own founds of our institution. From 26 patients, 20 patients agreed to consent inform to discontinuation of imatinib. 06 patients declined despite information because their insecurity about TFR. Twelve patients (60%) presented MR4. Median age was 52.3 years old and 13 (65%) were female. Median time diagnosis to discontinuation of imatinib 8.04(4.6-15.5) years. Twelve (60%) patients sustained TFR. Seven patients of twelve had presented MR 4 and five had MR 4.5 in the screening, respectively. (p = 0,85). It means 58,3% of the total of patients with MR 4 and 62,5% with MR 4.5. In this interim analysis the median time of follow up was 14.5 (2.7-18.8) months. One patient died due to COVID19 with major molecular response (MMR). Eight (40%) lost MMR and imatinib was restarted. In this group the median time until MMR loss was 7.24 (2.1-13.8) months. At this moment, 07 patients (87,5 %) recovered MMR. In addition, in this group 06 patients (75%) achieved the same level of MR with reintroduction of imatinib with median 5.2 (3.7-6.3) months. Regarding adherence, 4 (20%) had some absences in monthly medical consultations and 1(5%) missed follow-up. Fifteen tests (6.14%) were performed to confirm MR loss, however only in 8 tests (53.3%) were confirmed. In fact, 04 patients (33,33%) still in TFR because of the double confirmatory test. There was no transformation to advanced phases. Gender, age at de diagnosis, age at discontinuation, Sokal, BCR-ABL trasncripts type, duration of Imatinib therapy, duration of MR 4.0 or MR4.5 did not affect TFR. Withdrawal syndrome occurred in 05 patients (25%); 04 patients with grade 1 and 01 patient with grade 2, had been used corticosteroid for few days. The preliminary results of this trial demonstrated the feasibility and safety of Imatinib discontinuation, even using Brazilian copies, and the results were similar of that presented in another trials.

TREATMENT-FREE RESPONSE USING BRAZILIAN IMATINIB COPIES AS FIRST LINE -RESULTS FROM TWO PROSPECTIVE CLINICAL TRIALS

Several trials have demonstrated the feasibility of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients with a deep molecular response, but little data is available about the results using imatinib copies. Brazil has been using imatinib copies as a first-line treatment since 2013. To report the results of two Brazilian imatinib copies trials and to evaluate factors impacting treatment-free remission (TFR) and treatment-free survival (TFS) after imatinib discontinuation. From Dec-2016 until Oct-2018 (USP trial, NCT03239886) and from Oct-2020 until Apr-2021(Hemomed Trial- DIP), 51 eligible patients were included to participate in two trials of imatinib discontinuation. Inclusion criteria: age > 18 years, chronic phase, minimum of three years (USP trial) and four years (DIP) of imatinib copies therapy, a deep molecular response, defined as MR4.0 or MR4.5 sustained for more than 2 years, and a confirmatory test at the moment of the screening. Atypical transcripts were excluded. After discontinuation, patients on the USP trial were monitored by Q-PCR monthly for the first 6 months and bimonthly after 6 months for the first year and quarterly afterwards. Patients in DIP monitoring were monthly for the first year and every 2 months in the second year. Minimal criteria for IM re-initiation was loss of major molecular response (MMR) confirmed by two exams. Median age was 53 years at the time of discontinuation. 58% male (USP) and 65% female (DIP). Imatinibs therapy was 9.9 years (3-15.5 y). 52.9% had MR4.5 at the screening. TFS at 6 months was 78% (95 Cl 67-90), 12 months 66% (95 Cl 54-80) and at 24 months 54% (95 Cl 42-71). TFS by center at 12 months were 64.5 % (USP) and 67% (DIP). TFS according to previous molecular response after 24 months of follow-up (MR4 vs. MR4.5) (p =0,086). MMR recovery was present in 100% with a median time of 3.5 months. Four patients are still on TFR because the double testing of MMR loss was not confirmed. These two trials demonstrated the feasibility and safety of imatinib discontinuation, even using Brazilian copies, and the results were similar to that presented in another trial. The confirmatory exam to establish the loss of TFR was useful and safe. However, the results no suggest a benefit on monthly Q-PCR after six months of follow-up.

Discontinuation of imatinib in patients with oligo-metastatic gastrointestinal stromal tumor who are in complete radiological remission: A prospective multicenter phase II study.

11535 Background: Life-long tyrosine kinase inhibitor (TKI) treatment is recommended for patients (pts) with metastatic GIST. We investigated whether highly selected pts with metastatic GIST may remain in durable complete remission after imatinib discontinuation. Methods: In this 1-group, prospective, multicenter phase II trial (NTC02924714) selected pts with overtly metastatic GIST discontinued imatinib treatment. Eligible pts had been treated with imatinib &gt; 5 yrs for oligo-metastatic (≤3 metastases) disease, had no GIST progression and had undergone either R0/R1 resection or radiofrequency ablation (RFA) of all metastases, and had no longer detectable metastases on CT/MRI imaging, The primary endpoint was 3-yr progression-free survival (PFS), overall survival was a secondary endpoint. We estimated to achieve an improvement from 15% to 35% in 3-yr PFS compared to pts treated in the BRF-14 trial with a sample size of 31 pts. Results: The trial closed early due to slow accrual. Between January 5, 2017, and June 5, 2019, 12 pts (males, 7) with a median age of 67 yrs (range, 50-85) were enrolled. All pts had their primary tumor surgically removed (stomach, 4; small bowel, 6; large bowel/rectum, 2). Seven pts had KIT exon 11 mutation, 2 KIT exon 9 mutation, 1 PDGFRA exon 12 mutation, 1 had no mutation in KIT/PDGFRA, and 1 pt had unknown GIST mutational status. Eight pts had liver metastases, 3 peritoneal metastases, and 1 had both. Prior to enrollment all pts were in macroscopic complete remission after surgical metastasectomy (n = 7), RFA (n = 2), or both (n = 1), and 1 pt achieved complete radiological response with imatinib. At enrollment, 8 pts had imatinib 400 mg/d and 4 had &lt; 400 mg/d. The median time of imatinib treatment before study entry was 8 yrs (range, 5-17). After imatinib discontinuation 7 (58%) pts progressed; the median time to progression was 10 mos (range, 2-31 mos). Five (42%) patients were progression-free after a median follow-up time of 42 mos (range, 30-59 mos). Median PFS was 23 mos and the estimated 3-year PFS 39%. Patients who progressed all achieved a second remission after restarting imatinib and were alive after a median follow-up time of 48 mos (range, 32 to 61 mos). Conclusions: The findings suggest that discontinuation of imatinib is safe in highly selected patients with oligo-metastatic GIST and that such patients may survive without detectable GIST progression for several years. The findings need to be viewed with caution due to the small pt numbers. Further study on imatinib discontinuation seem warranted. Clinical trial information: NCT02924714.