TKI-therapy Duration Research Articles

The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60–82%) compared to patients with GG (51%, 95% CI: 41–61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

Concurrent BCR::-ABL1 and CBFB Rearrangement in De Novo Acute Myeloid Leukemia

Introduction Acute myeloid leukemia (AML) is known for its genetic heterogeneity. Several recurrent genetic variants have been characterized including AML-defining chromosomal rearrangements involving the core binding factor (CBF), such as inv(16)/t(16;16)/ CBFB:: MYH11. 1 Less common is a subset of AML characterized by the Philadelphia chromosome (Ph+), generating a BCR::ABL1 fusion protein. 2 The Ph+ AML subtype is associated with poor prognosis and treatment resistance. 3,4 Co-occurrence of CBFB rearrangement and BCR::ABL1 fusion is rare, representing a subgroup with unique clinical and molecular features. To date, there have been less than 30 cases reported in the literature. 5-8 Case Description A 62-year-old male presented to hospital with headaches, visual changes, weakness, and a nodular rash on his back, with leukocytosis, thrombocytopenia, and 42.5% circulating blasts. A bone marrow (BM) aspirate and biopsy was diagnostic of AML with 56% myeloblasts. RT-PCR was positive for an e19a2 BCR::ABL1 fusion transcript coding for p230 kDa fusion protein (p230) and CBFB: :MYH11 fusion gene transcript. Cytogenetics identified a complex karyotype with an inv(16) and a Ph chromosome (46,XY,t(1;14)(p32;q24),t(9;22)(q34;q11.2),inv(16)(p13.1q22)[10]), consistent with concurrent BCR::ABL1 and CBFB::MYH11 rearrangements within the same clonal population of cells. Treatment consisted of hydroxyurea for cytoreduction, 7+3 induction, one cycle of low dose cytarabine consolidation, and oral azacytidine maintenance, in combination with dasatinib. He did not receive Gemtuzumab ozogamicin (GO) given patient preference and comorbidities. Post-induction course was complicated by febrile neutropenia due to Enterococcus Faceium bacteremia, pre-renal acute kidney injury, and dasatinib-related complications including rash and transaminitis. These issues resolved by holding dasatinib for 15 days. Complete morphologic remission (CR) was obtained by Day 33 post-induction and no fusion gene transcripts were detectable by nested RT-PCR from BM aspirate on day 49 post-induction, nor day 76 post-consolidation The patient was ineligible for an allogeneic stem cell transplant given his poor performance status. At present, the patient remains alive and well, continuing on maintenance with oral azacytidine and dasatinib. Discussion We present the only case, to our knowledge, of a concurrent BCR::ABL1 p230 isoform and CBFB::MYH11 with de novo AML. Based on our literature search, 26 cases have been reported. BCR::ABL1 and CBFB::MYHII rearrangements in de novo AML potentially confers an intermediate to favorable prognosis with outcomes comparable to those of CBF-AML. Studies suggest that this entity may be more akin to AML with inv(16) rather than CML-BP with inv(16), thereby retaining favorable prognosis. 5,9-11 There are no formal guidelines for management of de novo AML with concurrent BCR::ABL1 and CBFB rearrangements. Traditional chemotherapy treatment strategies for Ph+ AML are often ineffective in these cases. The presence of BCR::ABL1 fusion transcript raises the possibility of utilizing TKIs targeting the BCR::ABL1 kinase domain. In our case, the patient achieved rapid CR with induction chemotherapy and dasatinib, but experienced multiple complications, precluding further intensive chemotherapy and allogeneic stem cell transplantation. This case raises a number of questions, including the optimal timing, combination, and duration of TKI therapy in the context of dual rearrangement de novo AML. This patient subgroup may benefit from intensive chemotherapy regimens and TKIs. Prospective monitoring of these cases is warranted to assess outcomes in comparison to Ph+ AML without coinciding CBFB rearrangement. This case report underscores the importance of comprehensive genetic profiling in Ph+ AML to determine the genetic landscape and individualize therapeutic strategies.

A Predictive Scoring System for Therapy Failure of Tyrosine-Kinase Inhibitors in Patients with Chronic-Phase Chronic Myeloid Leukemia

Background In the latest version of WHO criteria (5th edition, 2022), accelerated-phase chronic myeloid leukemia (CML-AP) was re-defined as “high-risk” chronic-phase chronic myeloid leukemia (CML-CP). However, there is no robust predictive scoring system for therapy failure of tyrosine-kinase inhibitors (TKIs) in these newly-defined CML-CP patients. Objectives To develop and validate a predictive scoring system for TKI-therapy failure in CML-CP patients. Methods Data from 2,038 consecutive CML-CP patients according to the WHO 2022 criteria receiving initially TKI-therapy at one centre were interrogated as the training dataset to develop a predictive scoring system which was subsequently-validated in 4,640 patients from 76 other centres (validation dataset). TKI-therapy failure was defined by the 2020 European LeukemiaNet recommendation. Results In the training dataset, 1,591 patients (78%) initially received imatinib; 326 (16%), nilotinib; 85 (4%), dasatinib; and 36 (2%), flumatinib (a novel 2G-TKI made in China). Median TKI-therapy duration was 58 months (IQR, 33-90 months). 515 patients (27%) experienced therapy failure at a median of 9 months (IQR 3-12 months) on TKI-therapy. Multi-variable analysis indicated that older age, male sex, lower hemoglobin concentration, higher proportion of blood blasts and basophils, larger spleen size below the costal margin and high-risk additional cytogenetic abnormalities (ACAs) in Ph + cells were significantly-associated with higher cumulative incidence of therapy failure. Based on the optimal Fine-Gray regression model, a formula to calculate the therapy-failure risk score was established: “ Initial TKI-therapy failure risk score = 1.9321 × (Age/100) + 0.2950 × Sex (male = 1, female = 0) - 0.8589 × (HGB/100) 2 + 0.0979 × Blood blasts + 0.023× Blood basophils + 0.0521 × Spleen size below the costal margin + 0.5075 × high-risk ACAs (existing = 1, no = 0)” which divided patients into low- (score ≤ 0.0545; n = 908; 47%), intermediate- (0.0545 < score < 1.1662; n = 791; 41%) and high-risk (score ≥ 1.1662; n = 216; 12%) cohorts with 7-year cumulative incidences of therapy failure of 8% (95%CI, 4, 12%), 39% (35, 43%) and 80% (76, 84%; p < 0.001; Figure 1A). Sub-distribution hazard ratios (sHRs) for therapy failure (low-risk cohort as reference) were 3.2 (2.6, 4.1, p < 0.001) and 9.5 (7.4, 12.2; p < 0.001) for the intermediate- and high-risk cohorts. In the validation dataset, 4,640 patients were classified into the low- (n = 2,168; 47%), intermediate- (n = 2,093; 45%) and high-risk (n = 379; 8%) cohorts using the scoring system. 7-year cumulative incidences of therapy-failure were 10% (7, 13%), 36% (33, 39%) and 70% (66, 74%; p < 0.001; Figure 1B). sHRs (low-risk cohort as reference) were 3.4 (3.0, 3.9; p < 0.001) and 8.8 (7.5, 10.3; p < 0.001) for the intermediate- and high-risk cohorts. Time-dependent AUROC values for therapy failure using the predictive scoring system were 0.84-0.92 and 0.79-0.86 in the training and validation datasets. Moreover, patients identified as intermediate- or high-risk cohorts by the predictive scoring system receiving initial 2G-TKI-therapy had significantly-lower therapy failure rate than those receiving imatinib-therapy ( p-values = 0.002 and 0.017) both in the training and validation datasets. Conclusions We developed and validated a robust predictive scoring system for TKI-therapy failure in newly-defined CML-CP patients according to the WHO criteria (5th edition, 2022), which might help physicians decide appropriate therapy strategy.

Patients with chronic myeloid leukemia and coronavirus disease 2019 in the Omicron era.

To explore the prevalence and severity of COVID-19 and the mental health during the Omicron pandemic in patients with chronic myeloid leukemia (CML), a cross-sectional survey from 2609 respondents with CML was performed. A total of 1725 (66%) reported that they had COVID-19 during this period. Among them, 1621 (94%) were mild; 97 (6%), moderate; 7 (0.4%), severe; and 0, critical or death. Four hundred three (15%), 199 (8%), and 532 (20%) had moderate to severe depression, anxiety, and distress, respectively. Eight hundred ninety (34%), 667 (26%), and 573 (22%), avoidance, intrusion, and hyper-arousal, respectively. In multivariate analyses, longer TKI-therapy duration was significantly associated with a lower prevalence of COVID-19 (odds ratio [OR] = 0.98; 95% confidence interval [CI], 0.95, 0.99; p = 0.043); however, living in urban areas (OR = 1.6 [1.3, 2.0]; p < 0.001) and having family members with COVID-19 (OR = 18.6 [15.1, 22.8]; p < 0.001), a higher prevalence of COVID-19. Increasing age (OR = 1.2 [1.1, 1.4]; p = 0.009), comorbidity(ies) (OR = 1.7 [1.1, 2.7]; p = 0.010), and multi-TKI-resistant patients receiving 3rd-generation TKIs or investigational agents (OR = 2.2 [1.2, 4.2]; p = 0.010) were significantly associated with moderate or severe COVID-19. Female, comorbidity(ies), unvaccinated, and moderate or severe COVID-19 were significantly associated with almost all adverse mental health consequences; increasing age or forced TKI dose reduction because of various restriction during the pandemic, moderate to severe distress, avoidance, or intrusion; however, mild COVID-19, none or mild anxiety, distress, avoidance, or intrusion. In conclusion, shorter TKI-therapy duration, increasing age, comorbidity(ies), or multi-TKI-resistant patients receiving 3rd-generation TKIs or investigational agents had a higher prevalence of COVID-19 or higher risk of moderate or severe disease in patients with CML; increasing age, female, comorbidity(ies), forced TKI dose reduction due to the pandemic, moderate or severe COVID-19, unvaccinated, a higher likelihood of worse mental health.

The First Results of Asciminib Therapy in Highly Pretreated Chronic Myeloid Leukemia Patients Under the Managed Access Program (MAP) in Russian Federation

Background: The problem of resistance and intolerance to 2nd generation tyrosine kinase inhibitors (2G TKIs) in patients (pts) with chronic myeloid leukemia (CML) currently remains relevant. Ponatinib has demonstrated a high effectiveness and may be an option in CML pts with resistance or intolerance to available TKIs but the high incidence of vascular adverse events (AEs) limits its broad use. A STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor asciminib has demonstrated a superiority over bosutinib in CML pts previously treated with 2 or more TKIs (Phase III Study). Asciminib is available in Russia under the Managed Access Program (MAP) approved by Novartis.Aim: to present the first results of the use of asciminib in clinical practice under the MAP program in Russia.Methods: In total 46 CML pts from 3 Russian clinics were enrolled into the MAP program and received asciminib from September 2019 to June 2021 (1 pt started asciminib in a cinical trial and was transferred to MAP later). We analyzed therapy results of 32 pts who received asciminib for at least 3 months. Patient recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR), major molecular response (MMR) and deep molecular response (MR4) rates were assessed by cumulative incident function (CIF). Differences between the subgroups were considered significant with p value ≤ 0.05 by the Gray's test.Results: Baseline characteristics: male: 41%; Меdian (Me) age 54 years (range 26-81); Me duration of CML before asciminib was 8 years (range 2-24); 23 pts were in chronic phase (CP) CML, 7 and 2 pts had a history of accelerated phase (AP) and blast crisis (BC), respectively, but were in a second CP at baseline. Nineteen (59%) pts had BCR-ABL mutations, 10 pts (31%) had BCR-ABLt315i clones, 7 (22%) pts had at least two mutations. Eight (25%) pts had additional chromosomal abnormalities (ACAs). Twenty one (66%) pts received ≥4 TKIs, 14 (44%) pts had a history of ponatinib treatment. Me duration of asciminib treatment at the time of analysis was 7 months (range 4-24), 4 (12.5%) pts discontinued asciminib due to lack of efficacy; all pts were alive. The initial asciminib dose was 40 BID in 22 (69%) pts and 200 mg BID in 10 (31%) pts.CCyR, MMR and MR4 at the time of analysis was achieved in 32% (8/25), 34% (10/29) and 17% (5/30) pts, respectively (considering pts without this kind of response at baseline). The 6 month CIF of CCyR, MMR and MR4 was 27%, 24% and 19%, respectively.Univariate analysis was performed in 29 pts without MMR at baseline evaluating the following factors of 6 month MMR achievement: initial dose of asciminib, CML phase, presence of BCR-ABL mutations and ACAs, best molecular response on previous TKIs, molecular response at the time of asciminib starting, history of ponatinib treatment, number of TKIs and duration of TKI therapy before asciminib. The duration and number of TKIs, the history of advanced phases, BCR-ABL kinase domain mutations and ACAs did not significantly effect on MMR rate (tab.1). BCR-ABL<1% on previous TKIs (54% vs 0%, p=0.0008, hazard ratio 20.9 (2.6-170)) and BCR-ABL<10% at the time of asciminib start (44% vs 15%, p=0.035, hazard ratio 3.8 (1.05-13.6)) were found as a predictive factors for MMR at 6 month.Fourteen (44%) of 32 pts had AEs of any grade and 7 (22%) had AEs of grade 3-4 (hematological AEs -6 (19%), non-hematological AE- 1 (3%)) (tab.2).Conclusion: Asciminib has shown promising efficacy and a good toxicity profile in a cohort of highly pre-treated CML pts and should be considered as a therapeutic option for CML pts resistant or intolerant to other TKIs. [Display omitted] DisclosuresTurkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Chelysheva: Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau.

Highly Sensitive Droplet Digital PCR to Identify CML Patients with a High Probability of Achieving Treatment-Free Remission

Introduction: Treatment Free Remission (TFR) is the ultimate goal of therapy for most CML patients. Despite adopting consensus eligibility criteria of a sustained deep molecular response and more than 4 years of TKI therapy, the relapse rate after TKI cessation is still around 50%. More sensitive detection of residual leukaemia has the potential to improve our capacity to predict TFR outcomes for individual patients.Aim: To correlate droplet digital PCR (ddPCR) assay results with TFR outcome, especially in the setting of undetectable levels measured by qRT-PCR.Method: ddPCR was performed on blood samples from 51 TFR-eligible CML patients at the time of TKI cessation. 5 µg RNA per sample was used in 8 wells/sample using the BioRad QXDx BCR-ABL %IS kit on QX200 ddPCR system which yielded BCR-ABL1% (IS) directly. All these patients achieved MR4.5 that was sustained for ≥ 2 years.Results: 100% of patient were in MR4.5 via qRT-PCR at the time of stopping. 61% of the 51 patients evaluated relapsed within 12 months. Median duration of TKI therapy for the whole group was 5.8 years (range 2.2- 14 years). 20 patients achieved TFR success with a median follow up of 24 months (TFR group; sustained BCR-ABL1 <0.1% (IS) after TKI discontinuation for ≥12 months), while 31 patients relapsed (Relapse group; BCR-ABL1 >0.1% (IS) after stopping; median time of relapse 3 months, range 1-10 months).A ROC curve analysis correlated TFR outcome with ddPCR results, with BCR-ABL1 level ≥0.003% via ddPCR at the time of stopping identified as an optimal cut-off. Kaplan-Meier analysis showed that 89% of the patients with ddPCR ≥0.003 relapsed after TKI cessation, whereas the ddPCR <0.003 demonstrated a significantly reduced relapse rate to 54% (p=0.01, Figure 1A). In addition, the TFR group (median BCR-ABL1 0.00065%) demonstrated approximately two-fold lower levels of BCR-ABL1transcript level compared to the relapse group (median 0.0012%). Interestingly, 7/31 (23%) of the relapsed group had undetectable BCR-ABL1 transcript even with the current highly sensitive method, while this undetectable level was only observed in 35% of the TFR group.We next assessed other known predictors of TFR success relative to ddPCR results in a Cox proportional hazard model. We have previously demonstrated that the BCR-ABL1 halving time after commencing therapy is highly predictive of TFR. At a univariate level, transcript type (e13a2 versus e14a2, p=0.01), BCR-ABL1 halving time (p>0.0001), and mRNA quantitation by ddPCR ≥ 0.003% (p=0.02) were all significantly associated with clinical outcome. Other variables including gender, age, ELTS score, Sokal score, MR4.5 duration and TKI duration were not associated with clinical outcome in this cohort (Figure 1B). In the multivariate analyses (Figure 1C), ddPCR remained an independent predictor after adjusting for ELTS, TKI duration and MR4.5 duration. Interestingly, ddPCR was not an independent predictor after adjusting for BCR-ABL1 transcript type or halving time.Conclusion: QXDx ddPCR assay is a promising tool for molecular residual disease monitoring in CML, especially when the BCR-ABL1 is undetectable by conventional method. The CML patients with levels of detectable BCR-ABL1 ≥0.003% measured by ddPCR have a significantly higher probability of relapse compared to patients with lower levels of the transcript. The ≥0.003% BCR-ABL1 level cut-off value could be a potential tool to aid decision-making when attempting TKI discontinuation in CML. However, even though a measurable level of BCR-ABL1 above 0.003% via ddPCR identified patients at high risk of relapse after a TFR attempt, it does not rule out the possibility of TFR; and a negative ddPCR result does not exclude the risk of molecular relapse. ddPCR may be most useful where other TFR predictive factors including BCR-ABL1 transcript type and halving time are not available.In-kind support was received from Bio-Rad for this study. [Display omitted] DisclosuresBranford: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cepheid: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes: Novartis: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria, Research Funding. Yeung: BMS: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria.

Variables Associated with Patient-Reported Symptoms in Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors

ObjectivesExplore the prevalence and severity of patient-reported symptoms in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs), and identify associated demographics and clinical variables.MethodsA cross-sectional questionnaire, including questions assessing demographics [sex,age, household registration, marital status, education level and co-morbidity(ies)], TKI used (imatinib versus nilotinib versus dasatinib; branded drugs versus Chinese generics versus foreign generics), interval from diagnosis to starting TKI, TKI-therapy duration, therapy response [complete molecular response (CMR) versus complete cytogenetic response (CCyR) but no CMR versus no CCyR] and common patient-reported symptoms, was distributed to patients with CML in the chronic phase (CP) across China and anonymously answered. Symptoms were reported as (1) not at all; (2) mild; (3) moderate and (4) severe. Patients with CML in the CP >18 years and receiving a TKI for ≥3 months were eligible. Multivariate logistic regression model was built to identify variables associated with each symptom.ResultsData of 1142 respondents were analyzed. 724 (63%) were male. 558 (49%) had ≥bachelor degree. Median age was 42 years (range 18-88 years). 859 (75%) were receiving imatinib, 183 (16%), nilotinib; 100 (9%), dasatinib; 761 (66%), branded drugs; 225 (20%), Chinese generics; 156 (14%), foreign generics, when they answered the questionnaire. Median TKI-therapy duration was 30 months (range, 3-192 months). 472 (41%) had achieved a CMR. The top 10 common patient-reported symptoms were fatigue (77%), periorbital and lower limb edema (72%), chest distress/shortness of breath (61%), memory deterioration (54%), skin color change (44%), alopecia (44%), muscle cramp (42%), weight gain (42%), musculoskeletal pain (42%) (Figure). In multivariate analyses, female (OR 1.5-2.7, p=<0.001-0.007), urban registration (OR 1.4-1.6, p=0.004-0.023), co-morbidity(ies) (OR 1.4-2.3, p=<0.001-0.049), interval from diagnosis to starting TKI ≥6 months (OR 1.6-1.9, p=0.013-0.016), foreign generics (OR 1.5-4.0, p=<0.001-0.027), longer therapy duration (OR 1.5-4.5, p=<0.001-0.048) were factors associated with more common and severer symptoms. Unmarried person (OR 0.2-0.7, p=<0.001-0.051), nilotinib (OR 0.1-0.7, p=<0.001-0.046), achieving a CCyR but no CMR (OR 0.5-0.8, p=<0.001-0.052) were factors associated with fewer and milder symptoms. Different ages were associated with different prevalence and severity of the symptoms. Education level ≥bachelor (OR 1.4-2.1, p=0.004-0.024) was associated with more common and severer symptoms of skin color change and hypermenorrhea (in female ≤50 years), however, fewer and milder symptom of weight gain (OR 0.76, p=0.031).Conclusions This survey showed that demographics, current TKI used, therapy response and duration were associated with the prevalence and severity of patient-reported symptoms in patients with CML receiving TKIs. These results will contribute to making treatment decisions and improving quality of care and patients' quality of life. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Point: Is there a best duration of deep molecular response to achieve therapy-free remission in chronic myeloid leukaemia?

Point: Is there a best duration of deep molecular response to achieve therapy-free remission in chronic myeloid leukaemia?

Outcome of Patients with Chronic Myeloid Leukemia in Lymphoid Blast Crisis (CML-LBC) and Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with Hyper-CVAD and Dasatinib

Outcome of Patients with Chronic Myeloid Leukemia in Lymphoid Blast Crisis (CML-LBC) and Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with Hyper-CVAD and Dasatinib

Variables associated with self-reported anxiety and depression symptoms in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy

Variables associated with self-reported anxiety and depression symptoms were explored in 1169 adults with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI)-therapy. The Self-Rating Anxiety Scale and Self-Rating Depression Scale questionnaires were used to measure anxiety and depression symptoms. Two hundred and fifty-one (22.4%) and 415 (37.1%) respondents reported anxiety and depression, respectively. In multivariate analyses, female sex, lower education level, comorbidities, advanced-line TKI-therapy, and longer TKI-therapy duration were significantly associated with more severe anxiety and/or depression. It is concluded that socio-demographics, comorbidities, advanced-line TKI-therapy, and longer TKI-therapy duration were significantly associated with anxiety and/or depression symptoms in CML patients receiving TKI-therapy.

CML-083: Prognostic Factors of Durable Treatment-Free Remission in CML Patients Based on the Prospective Study RU-SKI

Aim To define the prognostic factors for molecular relapse-free survival (MRFS) after TKI discontinuation in the Russian CML population. Methods The base for the analysis was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in patients (pts) with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic-phase, TKI therapy for at least three years and a stable DMR (BCR-ABL Results Three-year MRFS rate was 51%. Baseline pts characteristics: male - 50%; median (Me) age at TKI cessation 46 years (range, 22 to 80); Me duration of TKI therapy 8.3 years (range, 3 to 16.2); Me duration of DMR 3.2 years (range, 2 to 10.7). Therapy before treatment cessation: imatinib in 67 (68.4%) pts, second-generation (2G) TKI in 31 (31.6%) pts. Me follow-up time after TKI cessation was 40 mo (range, 28 to 57). Probability of MRFS (1st stop) was 53% after 36 mo of follow-up. Length of DMR, duration of therapy and depth of molecular response were found to be significant factors with p ≤ 0.05. We have found that the duration of TKI therapy, and not the duration of DMR, has an independent prognostic value for the Russian CML population due to the lack of molecular monitoring data at early stages of the disease. No difference in 36 months MRFS was observed in 1st-line imatinib (55%) compared with 1st-line 2G TKI (70%; p=0.26) and 2nd-line 2G TKI (39%; p=0,09) groups. However, significantly shorter treatment duration was observed in pts treated with 1st-line 2G TKI (Me=41.5 mo) vs imatinib (Me=96.4 mo), p Conclusion Longer treatment duration and depth of DMR before cancellation at least MR 4.5 are associated with durable TFR. Our study showed that the MRFS rate is not significantly improved with the use of 1st-line 2G TKI in comparison with 1st-line imatinib.

COVID-19 in persons with chronic myeloid leukaemia.

We studied by questionnaire 530 subjects with chronic myeloid leukaemia (CML) in Hubei Province during the recent SARS-CoV-2 epidemic. Five developed confirmed (N = 4) or probable COVID-19 (N = 1). Prevalence of COVID-19 in our subjects, 0.9% (95% Confidence Interval, 0.1, 1.8%) was ninefold higher than 0.1% (0, 0.12%) reported in normals but lower than 10% (6, 17%) reported in hospitalised persons with other haematological cancers or normal health-care providers, 7% (4, 12%). Co-variates associated with an increased risk of developing COVID-19 amongst persons with CML were exposure to someone infected with SARS-CoV-2 (P = 0.037), no complete haematologic response (P = 0.003) and co-morbidity(ies) (P = 0.024). There was also an increased risk of developing COVID-19 in subjects in advanced phase CML (P = 0.004) even when they achieved a complete cytogenetic response or major molecular response at the time of exposure to SARS-CoV-2. 1 of 21 subjects receiving 3rd generation tyrosine kinase-inhibitor (TKI) developed COVID-19 versus 3 of 346 subjects receiving imatinib versus 0 of 162 subjects receiving 2nd generation TKIs (P = 0.096). Other co-variates such as age and TKI-therapy duration were not significantly associated with an increased risk of developing COVID-19. Persons with these risk factors may benefit from increased surveillance of SARS-CoV-2 infection and possible protective isolation.

R-Interferon Treatment before Imatinib Reverses the Negative Impact of e13a2 Transcript Type on Treatment Free Remission Duration after Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia Patients

BACKGROUND Tyrosine Kinase Inhibitor (TKIs) discontinuation has become, nowadays, under proper conditions, a feasible option for chronic myeloid leukemia (CML) also in "real life" setting. Different papers investigated which factors (age, sex, type of TKI, previous r-interferonα -r-INFα- therapy, line of therapy at stop, type of transcript, duration of TKI therapy and of sustained deep molecular response -sDMR-, Sokal risk score) could predict a successful TKIs discontinuation either within protocols or outside of clinical trials, and the results are not unique. AIM We retrospectively evaluated our CML pts who stopped TKI after sDMR in order to assess the variables that could influence the probability of a durable TFR. METHODS BCR-ABL transcripts were determined by RQ-PCR performed according to EAC protocol (Gabert et al, 2003) and to the standards of the Italian National Network Labnet. Criteria for TKI discontinuation was sustained DMR (MR4 or better) for at least 2 years. After TKI withdrawal, RQ-PCR for BCR-ABL was performed every month during the first year and every 2 months thereafter. TKI treatment was reintroduced if DMR loss occurred.TFR was assessed using the Kaplan-Meier method; potential prognostic factors were considered for multivariable analyses at a level less than .20. RESULTS Between October 2010 and January 2019, 68 patients discontinued TKIs, 18 of them after less than 5 years of treatment because of pregnancy desire (3), intolerance (6), patient's desire/non compliance (5), enrollment in study protocols (4). At discontinuation median age was 63 years (30-85), median time from TKI start 85 months (30-190), median duration of sustained DMR 48 months (24-153). Sokal distribution was 48%, 31% and 18% for low, intermediate and high risk respectively (2 patient was not evaluable). E14a2 transcript type was present in 52 pts and e13a2 in 16 pts. Thirty-eight patients stopped imatinib, 25 nilotinib (19 in 1st line, 6 in 2nd line), 5 dasatinib. Before imatinib 15 patients received r-IFNα, for a median time of 60 months (3-256). Median follow up after TKI stop was 39 months (5-105, &gt;24 in 61, &lt;12 in only 2 patients). Twenty-eight (41%) patients lost DMR. Median time off-therapy for these patients was 3 months (1-19), only 2 lost DMR after 6 months (at +16 and +19 months). One patient aged 87 years has not yet resumed therapy but remains in stable MR3 at 34 months after TKI discontinuation. Therapy was restarted in 27 patients (1 in MR1, 11 in MR2, 15 in MR3), 24 achieved a second DMR after a median interval of 2 months (1-18); 3/27 patients are in M3 after 2, 22 and 26 months. Neither cytogenetic relapses, nor progressions were documented. One patient died in DMR for pancreatic cancer. Univariate analysis showed no difference in relapse risk according to age, gender, type of TKI (imatinib vs 2nd generation TKIs), and Sokal score, while the e14a2 vs e13a2 transcript type (p = 0.011), duration of TKI therapy &gt; 60 months (p = 0.025) and previous r-IFNα therapy (p=0.021) were significantly linked to better outcome after TKI discontinuation; sDMR &gt; 72 months is very close to be a significant variable (p=0.055). At multivariate analysis only the type of BCR-ABL transcript (p=0.027) and previous r-IFNα ( p=0.016) remained independent significant prognostic factors -figure A and figure B-. CONCLUSION e14a2 transcript type was confirmed as a robust favorable prognostic factor for TFR maintenance. In our experience, 2GTKIs didn't impact favorably TFR duration after TKIs discontinuation, conversely r-IFNα treatment before TKI improved the probability of maintaining DMR after TKI withdrawal, particularly in e13a2 patients. In fact r-IFNα before imatinib reversed the negative prognostic impact on TFR maintenance of the e13a2 transcript type. Disclosures D'Adda: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Daiichi-Sankyo: Consultancy.

PS1177 PROGNOSTIC FACTORS FOR MOLECULAR RELAPSE‐FREE SURVIVAL AFTER DISCONTINUATION OF TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA BASED ON RUSSIAN MULTICENTER PROSPECTIVE TRIAL (RU‐SKI)

Background:About 50% of chronic myeloid leukemia (CML) patients (pts) after TKI discontinuation lose a major molecular response (MMR) and should return to therapy. Despite the fact that, after TKI resumption, almost all pts re‐achieve deep molecular remission, facilitating a more accurate selection process for therapy cessation remains topicalAims:To define the prognostic factors for molecular relapse‐free survival after TKI discontinuation in Russian CML populationMethods:The base for the analysis was the Russian multicenter prospective study RU‐SKI on the discontinuation of TKI in pts with CML and deep molecular response (DMR). Ninety‐eight CML pts with chronic phase (CP), TKI therapy for at least three years and a stable DMR (BCR‐ABL&lt;0.01%) for at least two years were enrolled. Pts with previous imatinib failure and treatment‐free remission (TFR) failure were eligible. The BCR‐ABL level was evaluated by RQ‐PCR according to the international scale (IS). The schedule of molecular tests was as follows: monthly during the first six months (mo) after TKI cessation, every two mo from six to 12 mo and every three mo thereafter. Treatment by the same TKI was resumed in case of MMR loss (BCR‐ABL&gt;0.1%). We used the proportional hazards regression analysis to identify independently significant factors for molecular relapse‐free survival (MRFS). We categorized each independently significant factor into two groups, depending on the optimal cutoff level obtained by the minimum P‐value approach. We used the Kaplan‐Meier method for calculating the probability of MRFS and the log‐rank test for comparison.Results:One year MRFS in all group was 51%. MRFS rate in pts with history of previous TFR failure (n = 7) was 14%. We decided to exclude from multivariate analysis pts with history of previous TFR failure to identify significant factors for the first attempt of therapy cancellation. Baseline pts characteristics (1st stop, n = 91): male: 48%; median (Me) age at TKI cessation 46 years (range 22 to 80); Me duration of TKI therapy 8.3 years (range three to 16.2); Me duration of DMR 3.2 years (range two to 10.7). Therapy before treatment cessation: imatinib in 63 (69%) pts, second‐generation (2G) TKI in 28 (31%) pts. Me follow‐up time after TKI cessation was 24 mo (range 12 to 41). Probability of MRFS (1st stop) was 55% after 12 mo of follow‐up. We include in multivariate analysis the following factors: age, gender, history of previous resistance to imatinib, type and line of TKI, duration of therapy, length of DMR, depth of molecular response before cancellation, Sokal risk group. Sokal risk group, duration of therapy and depth of molecular response were found to be independently significant factors with p ≤0.05. Treatment duration more than 8 years, depth of DMR before cancellation at least MR4.5, non‐high Sokal risk group were attributed to favorable factors for MRFS after the optimal cutoff level was obtained (fig.1). We have found that the duration of TKI therapy, and not the duration of DMR has an independent prognostic value for the Russian CML population. The lack of molecular monitoring data at early stages of the disease in long‐term treated pts cause to the 1st DMR detection bias. Indeed, a longer time to the 1st DMR was observed in pts with the longer duration of TKI therapy (fig.2).Summary/Conclusion:Patients with treatment duration more than 8 years, depth of DMR before cancellation at least MR4.5, non‐high Sokal risk group and without history of previous TFR failure are more preferable for TKI discontinuationimage

PB1946 OUTCOMES FOLLOWING TREATMENT DISCONTINUATION IN CML: REAL‐WORLD EXPERIENCE FROM 3 REGIONAL UK CENTRES

Background:Emerging evidence from clinical trials has demonstrated the feasibility of TKI discontinuation in CML. However, real‐world data of treatment discontinuation has been limited, particularly where this is due to clinical considerations such as drug toxicities.Aims:To address the real‐world outcomes of treatment discontinuation and factors influencing this.Methods:We retrospectively analysed all patients from 3 hospitals in Birmingham, UK who have discontinued CML treatment since 2010.Results:Altogether 28 patients (11 males, 17 females) discontinued TKI. Prior to discontinuation, these patients received TKI for chronic‐phase CML for a median of 8.9 years (range 4.3‐15.2 years). At the time of discontinuation, 22 were receiving frontline TKI therapy while 6 patients had 1 or 2 prior treatments including interferon‐alpha, allogeneic SCT and other TKIs. Twenty‐two patients (78.6%) discontinued imatinib, and 3 patients each (10.7%) discontinued nilotinib and dasatinib respectively. The median age at the time of discontinuation was 61 (range 18‐83). The most common reasons for TKI discontinuation were patient preference (n = 10), enrolment in a TKI discontinuation trial (DESTINY; n = 9) and TKI drug toxicity (n = 8).Seventeen patients (60.7%) achieved MR4.5, 6 patients (21.4%) achieved MR4 and 5 patients (17.9%) had remission status below MR4 at the time of TKI discontinuation. Sixteen patients (57.1%) had been in deep molecular remission (MR4 or MR4.5) for at least 5 years prior to TKI discontinuation, including 11 patients (39.3%) who had been in MR4.5 for ≥5 years. Only one patient experienced withdrawal syndrome following discontinuation. With a median follow‐up of 2.5 years (range 0.2‐5.4 years), the median treatment‐free remission (TFR) was not reached. Ten patients (35.7%) experienced molecular relapse following TKI discontinuation, and in the majority (9 of 10) of these patients relapse occurred within 6 months of TKI discontinuation. All 10 patients were restarted on TKI, with 6 of 10 patients returning to a major molecular remission. With the exception of two patients who died of a second malignancy unrelated to CML, all patients remained alive.Remission status at the time of TKI discontinuation significantly predicted for the duration of TFR (p = 0.018). The relapse rate in the initial 6 months following TKI discontinuation was 18.5% (3 of 16 patients), 33.3% (2 of 6 patients) and 80% (4 of 5 patients) for patients in MR4.5, MR4 and &lt;MR4 respectively at the time of discontinuation. There was also a trend for the TFR to be positively associated with the total duration of TKI therapy (p = 0.057) and the duration at MR4.5 (p = 0.066) prior to TKI discontinuation. There was no significant association between TFR and the type or line of TKI at discontinuation, the patient's age or their reason for discontinuation.Of note, long‐term TFR was also observed following non‐TKI treatments, including in a single patient who remained in MR4 following discontinuation 3.8 years ago of interferon‐alpha which he received for 15 years. Prior to discontinuation, the patient had been in MR4 for 9.6 years.Summary/Conclusion:Overall, our results are largely consistent with published data on TKI discontinuation in CML, demonstrating feasibility of discontinuation in clinical practice. Importantly, outcomes following discontinuation significantly correlated with the depth and duration of remission at the time of TKI discontinuation. Given the paucity of real‐word data on treatment discontinuation in CML, our study may provide additional confidence to clinicians on treatment discontinuation.image

Epidermal growth factor receptor T790M mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China

To explore the effect of epidermal growth factor receptor (EGFR) T790M mutation status on non-small cell lung cancer (NSCLC) in Yunnan province of southwestern China. First, this study used the super amplification refractory mutation system (Super ARMS) polymerase chain reaction (PCR) and Droplet Digital PCR (dd PCR) to evaluate the T790M gene mutation, in plasmatic ctDNA samples from 212 cases of NSCLC. The association between T790M mutations and clinical parameters were further explored. Next, to investigate the mechanism of drug resistance that resulted from T790M mutation, subgroup analyses according to duration of medicine (EGFR-TKIs) were carried out. Finally, we also evaluate the effectiveness of blood-based circulating tumor DNA (ctDNA) on detecting the T790M mutation by calculating Super ARMS’s detection efficiency. We found that the T790M mutation rate was 8.4% (18/212) in overall patients. The T790M mutation was more frequent in patients with brain metastasis 30.0% (12/40) (p < 0.01). We found that post-TKI samples 42.8% (15/35) were associated with a higher T790M mutation rate (p < 0.01). Subgroup analysis showed that the duration of TKI therapy for 6 to 10 months 66.6% (8/12) (p < 0.01) and >10 months 75.0% (9/12) (p < 0.01) were also associated with a higher T790M mutation rate. Super ARMS’s sensitivity, specificity, PPV, NPV, and accuracy were 100.0%, 99.4%, 94.7%, 100.0%, and 99.5% respectively. Generally, the EGFR-T790M mutation was more common in NSCLC patients with brain metastasis and those who received TKI therapy for more than 6 months. Moreover, Super ARMS is a sensitive, efficient, and practical clinic method for dynamically monitoring T790M mutation status and effectively guiding clinic treatment.

Comorbidity profile and its impact on reported outcome in Chinese patients with chronic myeloid leukemia in chronic phase receiving tyrosine kinase-inhibitor therapy

目的评估中国服用酪氨酸激酶抑制剂（TKI）的慢性髓性白血病慢性期（CML-CP）患者共存疾病状况及其对患者报告结果（PRO）的影响。方法2015年9月至2016年3月，在全国范围内向正在服用TKI的成年CML患者发放无记名调查问卷，问卷内容包括人口学特征、常见共存疾病、TKI用药、费用、治疗反应、健康相关的生活质量（HRQoL，以SF-36量表评估）、患者对TKI治疗的满意度和TKI治疗对患者工作及生活的影响等。结果1 108例CML-CP受访者提供的问卷可供分析，男性701例（63.6%），中位年龄42（18~88）岁，TKI用药以伊马替尼为主（76.4%），中位服药时间为29（3~178）个月。300例（27.1%）受访者报告具有共存疾病，常见的依次为：高血压（30.3%）、糖尿病（21.0%）、冠心病（12.3%）、胃肠道疾病（12.3%）、肝病（11.7%）、肾病（8.3%）、脑血管病（6.7%）、肺病（5.7%）、血栓（1.3%），其他良性病为15.3%，其他肿瘤为8.0%，其中74例（24.7%）报告有≥2种共存疾病。多因素分析显示，具有除代谢综合征以外的其他良性共存疾病与较低的HRQoL评分和TKI治疗影响患者工作生活显著相关，但并未显著影响患者对TKI治疗的满意度。此外，女性和未获得完全细胞遗传学反应（CCyR）与较低的HRQoL评分显著相关，大学及以上学历和服药时间≥3年与较高的HRQoL评分显著相关；一二代TKI之间换药和未获得CCyR与患者对TKI治疗不满意显著相关，而免费用药与较高的治疗满意度显著相关；年龄<60岁和未获得CCyR与TKI治疗影响患者工作生活显著相关。结论中国成人CML-CP患者中27.1%具有共存疾病，不同的共存疾病种类对患者生活质量和TKI治疗对患者工作生活的影响不同。

Patients' and hematologists' concerns regarding tyrosine kinase-inhibitor therapy in chronic myeloid leukemia.

To explore patients' and hematologists' concerns regarding tyrosine kinaseinhibitor (TKI)-therapy and identify variables associated these concerns. Methods A cross-sectional questionnaire including 16 common issues related to TKI-therapy was distributed to adults with chronic myeloid leukemia (CML) receiving TKIs and hematologists treating CML patients and answered anonymously. Data from 1518 patient respondents receiving TKI-therapy ≥ 3months were analyzed. 939 (62%) were male. Median age was 42years. 72% were receiving imatinib. Median TKI-therapy duration was 27months. Data from 259 hematologist respondents were analyzable. 154 (59%) treated > 5 persons with CML per month. Median number of concerns was 5 (range 0-16) for both patients and hematologists. The top five issues for both cohorts were new drug development, stopping TKI-therapy, TKI-reimbursement policies, TKI-related adverse effects and long-term efficacy of TKIs. 12 issues attracted proportionally discordant attention between patients and hematologists. Patients were more concerned with TKI-reimbursement policies, price reduction of TKIs, TKI-related adverse effects, restrictions to daily life, CML knowledge and interpretation of laboratory data, whereas hematologists were more concerned with stopping TKI-therapy, TKI choice, monitoring, TKI dose-adjustment, quality of generics and switching between branded and generic TKIs. In multivariate analyses female sex [OR = 1.4 (1.1-1.7); p = 0.008], education level ≥ bachelor e[OR = 1.8 (1.4-2.2); p < 0.001], TKI-therapy duration 36-<60months [OR = 1.4 (1.0-1.9); p = 0.049] and having adverse impact on daily life and work [OR = 1.5 (1.2-1.8]; p = 0.001] were associated with greater numbers of patients' concerns. Our data suggested hematologists need to be aware of CML patients' concerns to improve their quality-of-life and patient-hematologist communication.

Higher out-of-pocket expenses for tyrosine kinase-inhibitor therapy is associated with worse health-related quality-of-life in persons with chronic myeloid leukemia.

To explore health-related quality-of-life (HRQoL) profiles and identify socio-demographic and clinical variables associated with HRQoL in persons with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). A cross-sectional questionnaire was distributed to adults with chronic-phase CML receiving tyrosine kinase-inhibitor (TKI) therapy >3months in complete cytogenetic response (CCyR). Respondents were anonymous. SF-36 Health Survey was used to measure HRQoL. Data from 828 respondents were analyzable. 524 (63%) were male. Median age was 42years (range 18-88years). 648 (78%) were receiving imatinib. Median TKI-therapy duration was 36months (range 3-178months). 638 (77%) paid some or all of their TKI costs. Annual out-of-pocket expenses >$4600 USD was associated with lower physical component summary (PCS; -2.8 to -3.8; P=0.0081 and 0.0009) and mental component summary (MCS; -2.1 to -4.3; P=0.0394 and 0.0080) in multivariate analyses. Other variables significantly associated with a lower PCS and/or MCS included: (1) female sex; (2) increasing age; (3) education level<bachelor degree; (4) co-morbidity(ies); and (5) generic drug use. TKI-therapy duration 3-5years was associated with higher PCS and MCS. Higher out-of-pocket expense for TKI therapy is significantly associated with worse HRQoL in persons with chronic-phase CML in CCyR receiving TKI therapy. These data indicate the importance of drug cost and health insurance policies on people's HRQoL.

Variables associated with patient-reported outcomes in persons with chronic myeloid leukemia receiving tyrosine kinase-inhibitor therapy.

Explore patient-reported outcomes (PROs), including health-related quality of life (HRQoL), satisfaction with therapy, impact of the therapy on work and daily life, and concerns related to the therapy and identify variables associated with PROs in persons with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). Across-sectional questionnaire was distributed to adults with chronic phase CML and answered anonymously. SF-36 Health Survey was used to measure HRQoL. Our focus was on the physical component summary (PCS) and mental component summary (MCS) components. Data from 819 respondents receiving TKI-therapy ≥3 months and achieving a complete cytogenetic response were analyzed. Median age was 42 years (range 18-88 years). 652 (80%) were receiving imatinib. Median TKI-therapy duration was 36 months (range 3-178 months). 629 (77%) paid some or all of their TKI costs. In multivariate analyses, female sex, increasing age, lower education level, increasing co-morbidities, concomitant medication, ≥3 symptoms, moderate or severe symptom, switch from imatinib to a second-generation TKI, and higher annual out-of-pocket expense of TKI were significantly associated with lower PCS and/or MCS. However, TKI-therapy duration 3-7 years was significantly associated with better well-being. Higher PCS or MCS score was significantly associated with higher satisfaction level with TKI-therapy and lessimpact of TKI-therapy on subject's daily life and work.In addition, adverse impact on daily life and work was significantly associated with more interests in TKI-therapy-related issues. Social-economic and clinical variables were significantly associated with PROs in persons with CML receiving TKI-therapy.