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Association between oligo-residual disease and patterns of failure during EGFR-TKI treatment in EGFR-mutated non-small cell lung cancer: a retrospective study
Abstract Background Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI. Methods Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 – 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated. Results A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P < 0.001), the lack of residual central nervous system metastases (P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites. Conclusions This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment.
Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS).Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria.Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups.Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.
Testicular metastases from renal cell carcinoma (RCC) are extremely rare. Tyrosine kinase inhibitors (TKI) are the cornerstone of systemic therapy for metastatic RCC. We report a case of testicular metastasis in a 72-year-old patient with RCC that developed 17 years after nephrectomy and response to TKI treatment, a retrospective literature search on testicular metastases from RCC, and the indirect evidence described in the literature on the efficacy of chemotherapy and target therapy on testicular lesions.
Abstract Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an "inflammatory status" during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs. Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status. Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients. After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082). Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. Figure 1 Figure 1. Disclosures Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.
Abstract Background. Over 50% of CP-CML patients will achieve a deep molecular response (DMR) at some point during treatment with Tyrosine Kinase Inhibitors (TKI), where DMR is defined as BCR-ABL1 transcript levels lower than 1/10000 (or MR4). Treatment discontinuation (TD) in CP-CML patients with stable DMR is successful in approximately half of cases, with a relapse free survival (RFS) of 48-61% at 3 years. TD is considered safe, since MMR is achieved in almost all cases when TKI re-initiation is required. As such, treatment-free remission (TFR) is now usually attempted outside of clinical trials and is part of many CML guidelines. The progression to accelerated phase/blast crisis (AP/BC) after TD was considered virtually impossible for a long time. However, recent reports document at least six cases of disease progression after TD, some of which were fatal. These observations raise concerns about the safety of TD, since now the practice can no longer be considered completely immune from the risk of disease progression, an occurrence that drastically changes the patient situation and perspective when it develops. To best counsel patients and more safely apply TD, a precise quantification of the risk of progression in this setting is needed. Study Design and Methods The TFR-PRO project monitor CML patients in long term treatment and with stable DMR, followed at 28 centers in 4 different countries (Canada, Italy, Germany, Spain). Each center is expected to enroll approximately 100 patients. The following variables were measured: time adjusted rates (TAR) of molecular relapse (loss of MR3) and of progression to AP/BC; progression free and overall survival. Primary Objective To quantify the risk of progression to AP/BP, expressed as TAR, after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt. This value will be compared to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment. A flexible statistical approach will allow to attribute patients to the two groups according to their decision about TKI discontinuation and to the loss of MR3. Patients eligibility includes a history of at least 3 years of TKI treatment and at least 18 months of continuous DMR. Results The study opened on July 24 th,2020. Twelve centers are presently active with 303 eligible patients registered, for a total of 1614 person years available for analysis. Median follow up is 4.99 years (range 0.39-15.00 years), median age at diagnosis is 50.4 years and 47.9% patients are female. Sokal score (available in 147 patients) is low in 44.90%, intermediate in 32.65% and high in 22.45%. A total of 116 patients (38.28%) attempted TD at some point; 10 patients (3.30%) attempted TD twice. Loss of MR3 occurreded in 44/116 (37.93%) patients after TD for a TAR of 15.69/100 person years, (95% confidence interval (CI) [11.68-21.09]), but also in patients who did not attempt TD (21/187, or 11.23%), TAR: 1.83/100 person years, 95%CI [1.19-2.81], p<0.0001. No patient progressed to AP/BC and therefore the TAR of progression is 0% with an upper value of 95%CI of 1.07/100 person years for patients who attempted TD, and with an upper value of 95%CI of 0.26/100 person years for patients who did not attempt TD. Conclusions These preliminary results obtained in a real world scenario indicate that approximately 40% of eligible patients attempt TD. The loss of MR3 after TD seem to happen less frequently (38%) than previously reported. Patients who discontinue treatment have a significantly higher risk of losingMR3 than those who continue treatment, and the risk of progression to AP/BC is lower than 1.07/100 person years. More patients need to be enrolled in this study in order to better estimate this latter number. Disclosures Assouline: Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment; Johnson&Johnson: Current equity holder in publicly-traded company; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Abruzzese: Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy.
Abstract Background: FLT3 tyrosine kinase inhibitors (TKIs) have improved outcomes in clinical trials for patients with FLT3 mutation-positive acute myeloid leukemia (FLT3mut+ AML). Gilteritinib is the first FDA-approved (11/28/2018) targeted therapy for relapsed/refractory (R/R) FLT3mut+ AML in adults, although two other multikinase inhibitors, midostaurin and sorafenib, are used off-label in this population. This analysis characterized treatment duration for these three drugs in R/R FLT3mut+ AML, as little is known about the treatment of patients receiving a FLT3 inhibitor in the real world. Aim/Objective: To describe real-world treatment patterns of patients newly initiating a FLT3 TKI for R/R AML following the launch of gilteritinib. Methods: This was a post hoc analysis of a US-based retrospective cohort study using IBM MarketScan claims data (1/1/2007-10/30/2020) to evaluate real-world treatment patterns. Adult patients (≥18 years) with R/R AML who newly initiated a FLT3 TKI (ie, ≥1 claim for gilteritinib, midostaurin, or sorafenib) on or after 12/1/2018 were eligible for inclusion. Included patients were required to have continuous enrollment starting 180 days prior to first AML diagnosis through first FLT3 TKI initiated for R/R AML on or after 12/1/2018 (index date). FLT3 TKI treatment duration was calculated as the difference between the first claim and the last day of supply or end of enrollment/study, whichever occurred first. Treatments that were not discontinued prior to the end of the study period (10/30/2020) were censored. Treatment duration was estimated using Kaplan-Meier analysis, and the hazard ratio for discontinuation was estimated with a Cox proportional hazards model. Additional subgroup analyses were conducted based on prior FLT3 TKI exposure for R/R AML and use of FLT3 TKI therapy alone or in combination with chemotherapy. Data from the ProMetrics specialty pharmacy database (12/6/2018-3/3/2021) were also analyzed to establish a benchmark for gilteritinib and validate the treatment duration in the MarketScan results. Results: A total of 65 patients newly initiating FLT3 TKIs for R/R AML were identified in the MarketScan database. Mean patient age was 53.4 years and mean Quan-Charlson Comorbidity index score at baseline was 5.1. Most patients initiating FLT3 TKI therapy received gilteritinib (n=44 [68%]). Patients initiating gilteritinib compared with other FLT3 TKIs had the highest prior history of high-intensity chemotherapy (n=24 [47%]) and hematopoietic stem cell transplantation (n=16 [31%]). Midostaurin was the most common prior TKI for patients who initiated sorafenib (n=6 [50%]) or gilteritinib (n=28 [55%]). The median (95% CI) treatment duration was 150 (73-260) days for gilteritinib (n=51), 60 (15-210) days for sorafenib (n=12), and 54 (28-268) days for midostaurin (n=12). Treatment duration was significantly longer for patients receiving gilteritinib compared with midostaurin (P=.0018) and sorafenib (P=.0016) in the Cox proportional hazards model (Table) and the Kaplan-Meier analysis (P=.0021) (Figure). Differences in gilteritinib duration in patients with prior TKI treatment versus no prior TKI treatment and patients who used a FLT3 TKI alone versus in combination with chemotherapy were not statistically significant (Table). The median gilteritinib treatment duration in the MarketScan data (150 days) was aligned with the median duration in the ProMetrics specialty pharmacy data (154 days), which validates the MarketScan results. Conclusions: This early look at treatment patterns suggests a median duration of therapy for gilteritinib of 150 days. Importantly, gilteritinib treatment duration does not appear to differ based on prior TKI treatment or overlapping use with chemotherapy. Small sample sizes precluded adjusted comparisons between the treatments. Gilteritinib was the most commonly used treatment. The availability of new targeted therapies such as gilteritinib is promising for patients with R/R FLT3mut+ AML and is changing the therapeutic landscape for this aggressive AML subtype. Figure 1 Figure 1. Disclosures Grinblatt: Astellas Pharma, Inc.: Consultancy; Bristol Myers Squibb: Consultancy; Astra Zeneca: Consultancy; AbbVie: Consultancy. Han: Astellas Pharma, Inc.: Current Employment. Nimke: Astellas Pharma, Inc.: Current Employment. Feng: Astellas Pharma, Inc.: Current Employment. Sullivan: Astellas Pharma, Inc.: Current Employment. Pandya: Astellas Pharma, Inc.: Current Employment.
Abstract Introduction Following the launch of the TKI's (tyrosine kinase inhibitors) for the treatment of CML (Chronic myeloid leukemia), establishing its significant control over the disease as evident by multiple studies such as the population based Swedish CML registry reporting that Patients reaching 70 years of age had a relative survival close to 1.0 compared to the normal population with the same age. Consequently, other dimensions have emerged regarding the safety of treatment, particularly the effect on Male fatherhood. This study was conducted to review the real-life data on the effect of TKI on the fatherhood of male patients in the National Center of cancer care and research (NCCCR) in Qatar in the period of 1st of January 2005 - 1st of January 2020. Up to our knowledge, this is the first study addressing the effect of TKI on fatherhood in patients with CML. Methods A single-center study, conducted a mixed-design (retrospective+ phone interviews) with CML male patients in the Chronic or accelerated phase, being followed up in NCCCR, evaluating the effect of Imatinib, Dasatinib, nilotinib, on their fatherhood whether they are taking it as first, a second, or third line of treatment. Inclusion Criteria: -Male patient diagnosed with CML, in Chronic or accelerated phase; 18 years of age or older and actively receiving tyrosine kinase inhibitors including (Imatinib, dasatinib, nilotinib) with the following: -Patients with no known issues with regards to fertility, (fertility is intact) will be included in the study. -Patients who developed fertility issues after the diagnosis of CML and starting TKI's. He has been evaluated by an andrologist and his evaluation concluded its TKI related. Exclusion criteria: -Patients with other MPNS. -Patients not fulfilling inclusion criteria as follow: -Patient known to have infertility before the diagnosis of CML -Patient with infertility after Diagnosis of CML: If a clear underlying cause, not TKI related, will be excluded from the studyif no evaluation was done for infertility and it is not clear whether the infertility is related to an underlying cause or TKI and no proper evaluation by andrologist done excluded from this study The mother has documentation by gynecologist for infertility, or after examining the abortion, still-birth, or IUFD and checking the chromosomal analysis (any mother related cause whether endogenous or exogenous has been excluded) Results: 150 patients were interviewed to be included in the study, 22 (14%) patients had concerns related to medications safety and possible transmission of the disease, 33 (22%) patients had their families completed by the time of diagnosis. 26 patients have met the inclusion criteria, median age around 44 years, median age at diagnosis was 33.5. 100% were in chronic phase, 42.3% were on imatinib, 34.6% on Nilotinib, and 23.1% on Dasatinib. The median TKI exposure period before pregnancy was 3 years. Median age at first conception post TKI treatment is 36, with a median duration of TKI treatment around 7 years. offspring's total number was 43, 97.6% were full-term, had a normal delivery, and normal average weight at delivery. No stillbirths, fetal demise, or congenital anomaly were reported. All offspring had normal development and growth. Median age of children after CML diagnosis around 7 years. No reports of any CML-related cancer in all the offspring Conclusion: Around 98% of male CML patients taking imatinib, Dasatinib, Nilotinib had their offspring born normally with no delivery complications noted, all had no congenital anomaly, had normal growth and development, and no CML-related cancers were diagnosed. Further studies with a larger sample size are required to shed light on the TKI outcome on fatherhood in CML patients. Nonetheless, a call for attention for better education to patients starting on TKI's addressing the possible psychological fear or concerns of having an unsatisfactory effect on their fertility/offspring, targeting better acceptance and adherence to treatment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
Abstract Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). Around 40-60% of patients with stable DMR [deep molecular response, corresponding to <0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with recommendations from the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European Stop TKI) trial, 62% were in major molecular response (MMR: <0.1% BCR-ABL1 IS) at 6 months. DMR duration before TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up. Aims: The main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal than 40% and less or equal than 35%, respectively. Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74, DMR not confirmed n=11, atypical/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years). Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without MMR loss. At 6 months, 713 patients were available (without molecular test at 6 months: n=6, TKI restart without relapse: n=9). Since 434 patients (61%) [95% CI: 57-64] remained without relapse during the first 6 months, the null hypothesis was rejected (p<0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42-49], the null hypothesis of 35% or less was rejected (p<0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred. Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis. Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years. Figure 1 Figure 1. Disclosures Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Novartis: Research Funding; BMS: Research Funding; Janpix: Research Funding; Pfizer: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
Abstract Introduction: Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with chronic myeloid leukemia in chronic phase (CML-CP). The advent of TKIs has led to improvements in survival, with a life expectancy nearly matching that of the general population. However, TKI failure rates increase with subsequent lines of therapy, leading to worse overall survival in patients in later lines of therapy. There are 5 approved TKIs (imatinib [IMA], bosutinib [BOS], dasatinib [DAS], nilotinib [NIL], and ponatinib [PON]) that may be used based on patient characteristics. IMA is frequently used in first-line (1L) therapy. Second-generation TKIs (BOS, DAS, and NIL) can be used in the 1L or second line (2L) depending on choice of 1L therapy. Use of PON is reserved mostly for patients with T315I mutations due to its adverse event profile. However, little guidance exists concerning which TKI to use in the third line and beyond (3L+). Here we present the results of a real-world evidence study of treatment patterns of TKIs in patients with CML-CP initiating 3L+ TKI therapy. Methods: This is a noninterventional, descriptive cohort study based on secondary use of data from 3 existing CML registries (Czech INFINITY, Dutch PHAROS, and Swedish CML). The observation period was from January 1, 2008, until the last available date of follow-up for each registry (6-12 years depending on the registry). Patients aged ≥18 years with CML-CP initiating a 3L TKI after registry enrollment were included in this analysis. Exposure was defined by TKI treatment with IMA, DAS, NIL, BOS, and PON. Descriptive statistics were used to describe patient demographics and treatment duration. Alluvial diagrams were used to describe and represent all treatment patterns. Results: Of those patients that had started a 2L TKI in the INFINITY, PHAROS, and Swedish CML registries, 109 (28.1%), 51 (35.7%), and 182 (12.8%) patients began 3L TKI therapy, with 105, 48, and 172 eligible patients, respectively, included in this study. Median age at diagnosis was 54.0, 61.0, and 59.6 years, respectively (Table 1). There were more men than women across all 3 registries (51.4%, 58.3%, and 50.6% vs 48.6%, 41.7%, and 49.4%, respectively). No agreement in treatment sequencing was seen across the 3 registries. However, across all 3 registries, the most frequently prescribed TKI in the 3L+ setting was NIL (52.4%, 59.6%, and 45.4%, respectively), followed by DAS (38.1%, 17.0%, and 32.6%, respectively). BOS (11.4%, 0%, and 27.9%, respectively), and PON (13.3%, 17.0%, and 11.1%, respectively), which were prescribed at varying frequencies across the registries. The alluvial plot in the Figure presents the sequence of TKI treatments for patients starting a 2L TKI. Median treatment duration in the 3L was longest for patients receiving NIL (27.5, 13.1, and 45.0 months, respectively) and DAS (26.6, 10.0,9.9 and 40.9 months, respectively), except in PHAROS, in which PON resulted in a longer treatment duration than DAS (6.0, 11.4, and 7.2 months, respectively). In INFINITY, rates of resistance (R) and intolerance (I) in patients discontinuing therapy with BOS, DAS, and NIL were 28.6% and 42.9%, 61.1% and 38.9%, and 48.0% and 36.0%, respectively. In PHAROS, 100.0% of patients discontinued DAS and IMA in the 3L due to I, while R and I were reasons for discontinuation in 16.7% and 83.3% of patients discontinuing NIL and 66.7% and 33.3% of patients discontinuing PON, respectively. The Swedish CML register reported that 15.8%, 9.1%, and 33.3% of patients discontinued DAS, NIL, and PON, respectively, in the 3L+ due to I (Table 2). Conclusions: Based on these real-world treatment patterns (which may provide insights into TKI access in various settings), patients in the 3L were most frequently treated with the second-generation TKIs NIL and DAS, with a smaller proportion treated with BOS and PON. However, no common agreement in sequencing of TKI treatment was seen across the 3 registries. Duration of treatment was longest in patients receiving NIL and DAS. Treatment discontinuation occurred frequently due to both R to and I of the 3L TKI used. Between 12.8% and 35.7% of patients that started a 2L TKI required 3L+ therapy, and therefore additional treatment options that are efficacious and well tolerated are needed for these patients. This study was a research collaboration between Novartis and the 3 registries and was funded by Novartis. Figure 1 Figure 1. Disclosures Dahlen: Novartis: Research Funding. Ferreira: Novartis: Consultancy; Roche: Consultancy; MerckGroup: Consultancy; Research institute for the study of genetic and malignant disorders in children.: Consultancy. Westerweel: Pfizer: Consultancy; BMS / Celgene: Consultancy; Incyte: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding. Sahmoud: Novartis: Current Employment; H3 Biomedicine: Consultancy; Context Therapeutics: Consultancy. Wormser: Roche: Current equity holder in publicly-traded company; Novartis: Current Employment, Current equity holder in publicly-traded company. Žácková: Novartis: Speakers Bureau; Angelini: Consultancy, Speakers Bureau.
