2nd Generation Tyrosine Kinase Inhibitors Research Articles

Chronic Myeloid Leukemia Presenting with Megakaryocytic Blast Crisis: a Case Report with a Favorable Outcome

Chronic myeloid leukemia (CML) belongs to the chronic myeloproliferative neoplasms, a clonal disorder of pluripotent hematopoietic stem cells, arising because of a hallmark genetic anomaly- reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, which generates the BCR::ABL fusion gene. The disease can have a biphasic/triphasic evolution, comprised of an accelerated phase and a terminal blast phase (usually biphasic when blastic phase is lymphoid in nature). Most cases present during the chronic phase of the disease, with only 10% of cases presenting in the blast phase. Megakaryocytic blast crisis is an unusual form of presentation, accounting for less than 3% of cases and it commonly carries an unfavorable prognosis compared to the classic myeloid, lymphoid or even mixed lineage blast crises. Aim: To bring forth an unusual case of CML presenting with megakaryocytic blast crisis and the therapeutic challenges associated with this particular presentation, unexpectedly ending with a favorable outcome. Matherial and methods: we hereby present the case of a 50 year old female patient, diagnosed in 2015 with CML- megakaryocytic blast crisis, who underwent treatment with a tyrosine kinase inhibitor (TKI)- imatinib and intensive chemotherapy regimen 3+7, without satisfactory response. A second induction chemotherapy regimen followed (MEC), alltogether with the same TKI and cytoreductive treatment (hydroxyurea/HU), but still without achieving a complete remission. Thus, the TKI was switched to dasatinib and complete normalisation of blood counts followed (including thrombocytes). However, there was still inadequate molecular and cytogenetic response. Therefore, TKI dosage was increased and after 4 months the patient achieved complete remission, with no detectable BCR::ABL transcript. She spent 9 years on the same TKI until important pleural effusion developed, which required switching to another 2nd generation TKI- bosutinib, based on the patients age, genetic profile and commorbidities. She is still in complete remission without detectable BCR::ABL transcript/Philadelphia chromosome to this day (2024). Results and conclusions: this is the case of a rare presentation of CMLmegakaryocytic blast crisis, who underwent both TKI and intensive chemotherapy induction regimens, marked by a favorable unexpected outcome.

Allogeneic stem cell transplantation is still a highly curative therapy in adults with philadelphia chromosome-positive acute lymphoblastic leukaemia.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.

Comparison of morbidity and results of chronic myeloid leukemia treatment in Novosibirsk and the Novosibirsk region

   Introduction. Over the past decade significant progress has been made in the treatment of patients with chronic myeloid leukemia (CML). In the most patients it is possible to reach a major molecular response (MMR) and maximize overall survival (OS). However, in real clinical practice in the regions of Russia, there is a number of unresolved problems that have led to the deterioration in the results of therapy such as, low patient compliance to treatment and the lack of proper control by doctors of polyclinics over the intake of medications and the course of the disease.   Aim — to compare the incidence and results of therapy of patients with chronic myeloid leukemia in Novosibirsk and the Novosibirsk region.   Materials and methods. The results of therapy of 333 CML patients were studied. The incidence and prevalence of disease, 5-year OS and predicted 10-year OS as well as 5-years and 10-years predicted event-free survival (EFS) have been evaluated. Results of therapy and compliance to treatment of 214 patients with CML who had been treated with imatinib for more than 18 months also were studied.   Results. The incidence from 2004 for 2020 was 0.62 per 100,000 population per year, the prevalence of CML in Novosibirsk over the past 15 years has increased from 3.27 to 10.89 cases per 100,000 population, in the Novosibirsk region – from 1.83 to 5.55 cases per 100,000 population. Median OS was not reached. The 5-year OS and 10-year OS in Novosibirsk were 85.7 and 72.5 %, respectively. The 5-year OS and 10-year OS in Novosibirsk region was 80.5 and 72.3 %, respectively. The 5-year EFS and 10-years predicted EFS in Novosibirsk was 55.8 and 40.8 %, respectively. The 5-year EFS and 10-years predicted EFS in Novosibirsk region was 34.9 and 18.7 %, respectively (p = 0.02882). The median EFS in Novosibirsk and Novosibirsk region was 6.8 and 2.7 years, respectively. Among patients treated in Novosibirsk, 134 patients (95.7 %) achieved a complete clinical and hematological response (CHR), 124 patients (88.5 %) — a complete cytogenetic response (CCyR), 95 patients (67.8 %) achieved MMR. Treatment failure was in 45 patients who did not obtain MMR and 16 (35.5 %) of 45 did not achieve even CCyR. The 2nd generation tyrosine kinase inhibitors (TKI 2) were administered to 18 patients who were resistant to imatinib. CHR was maintained in 17 out of 18 patients (94.4 %), CCyR — in 14 patients (77.7 %), MMR was achieved in 12 patients (66.7 %). In Novosibirsk region CHR was obtained in 72 of 74 patients (97.3 %), CCyR — in 50 patients (67.6 %), MMR — in 13 patients (17.6 %). No MMR was achieved in 61 patients (82.4 %), 17 (22.9 %) of them failed to obtain even CCyR. TKI 2 were administered to 7 out of these 61 patients, and 6 (85.7 %) of 7 maintained CHR, 5 patients (71.4 %) — CCyR, 1 patient (14.3 %) – MMR. Adherence to imatinib therapy was significantly lower in the group of patients with therapy failure than in patients with an optimal response both in Novosibirsk (p &lt; 0.00001) and in Novosibirsk region (р = 0,000002).   Conclusion. We have revealed a significant increase in the incidence of CML in Novosibirsk and Novosibirsk region. The problems in treatment are as follows: insufficient control by primary care physicians over patients living in Novosibirsk region and low treatment compliance of patients.

Dasatinib: a potential tyrosine kinase inhibitor to fight against multiple cancer malignancies

Dasatinib is the 2nd generation TKI (Tyrosine Kinase Inhibitor) having the potential to treat numerous forms of leukemic and cancer patients and it is 300 times more potent than imatinib. Cancer is the major cause of death globally and need to enumerate novel strategies to coping with it. Various novel therapeutics introduced into the market for ease in treating various forms of cancer. We reviewed and evaluated all the related aspects of dasatinib, which can enhance the knowledge about dasatinib therapeutics methodology, pharmacodynamic and pharmacokinetics, side effects, advantages, disadvantages, various kinds of interactions and its novel formulations as well.

First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]

Somatic Mutations in Myeloid Transcription Factors and in Activated Signaling Pathway, but Not in Epigenetic Modifier Pathway, Predict the Risk of Treatment Failure and Progression to Advanced Phase in Chronic Myeloid Leukemia

Background Next-generation sequencing (NGS) is currently reforming contemporary clinical practice into precision medicine incorporating genomics-based knowledge into the clinic. Recently, multiple studies showed that mutations in epigenetic modifier genes are associated with poor treatment outcomes following tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML), particularly after Imatinib treatment. However, it is uncertain whether they either originated from clonal hematopoiesis or the CML clone. For example, ASXL1 mutation is the most recurrent mutation at CML diagnosis, and its presence is correlated with adverse prognosis in CML. Finding of rapid reduction in ASXL1 allele frequency following TKI therapy (Kim et al, Blood 2017) raises the question of whether it is a real driver of treatment failure in CML or not. In addition, it is of interest whether 2nd generation TKI (2G-TKI) therapies can abrogate the adverse impact of somatic mutations in CML. Accordingly, the present study attempted to evaluate the prognostic impact of mutation profiles on clinical outcomes in CML patients treated either with Imatinib or 2G-TKIs. Patients and Methods Our cohort includes a total of 394 samples including 254 samples collected at initial diagnosis and 140 samples taken during follow-up from 309 CML patients in two CML treating centers. Disease characteristics and treatment outcomes were evaluated and compared according to mutation profiles at initial diagnosis and during follow-up after TKI therapy. Treatment outcomes include any response with respect to major molecular response (MMR), molecular response (MR) with 2-log/deeper (MR2) or 4-log/deeper (MR4) with any lines of TKI therapy, failure-free survival (FFS), progression and overall survival (OS). Instead of conventional NGS, we applied smMIP-based NGS (limit of detection up to 0.2%) using our in-house CML-specific panel targeting 40 genes including epigenetic modifiers, myeloid transcription factors (TFs), tumour suppressors, genes in activated signaling, spliceosome and, cohesin complex. ResultsPatient group and treatment summary Summary of patient characteristics are as follows: median age of 54 years; male:female n=143/111 (56.3:43.7); disease status at presentation includes chronic- (n=233; 91.7%), accelerated- (n=15; 5.9%), blastic phase (n=4; 1.6%), or N/A (n=2; 0.8%); Sokal score, low (n=61, 24.0%), intermediate (n=84, 33.1%), high (n=74, 29.1%), or N/A (n=35, 13.8%). Frontline therapy includes Imatinib (n=190; 74.8%), or 2G-TKI (n=62) including Dasatinib (n=15; 6.0%), Nilotinib (n=37; 14.7%), Bosutinib (n=10; 4.0%), or other (n=2; 0.8%). Mutation profiles and their correlation with clinical outcomes following TKI therapy70 mutations were detected in 57 (22.4%) out of 254 diagnostic samples, while 64 mutations were detected in 39 (27.9%) out of 140 follow-up samples.Any mutation detected at initial diagnosis is associated with worse outcomes following TKI therapy. The adverse impact of somatic mutation was mainly from myeloid TF or activated signaling pathway mutations. Patients having those mutations at initial diagnosis showed higher risks of treatment failure (HR 2.8 95% CI [1.4-5.4], p = 0.003) and progression (HR 3.1 95% CI [1.1-9.1], p = 0.04), mainly when treated with Imatinib. On the other hand, the adverse impact of epigenetic modifiers was not apparent although a trend was observed toward a lower response rate for MR2 and MMR in patients carrying mutations in epigenetic modifiers.The adverse prognostic impact from these mutations seems to be abrogated by the use of 2G-TKI therapy, supporting the use of smMIP-based NGS for upfront TKI selection in newly diagnosed CML patients.In the cross-sectional analysis of follow-up samples, overall mutation frequency was significantly higher in the treatment failure or progression group compared to the optimal responders (p=0.012), suggesting longitudinal tracking of mutation profiles may help identify cases of impending treatment failure or progression early. Conclusion Our study shows that mutation profiling utilizing smMIP-based NGS can help identify patients with a potential adverse prognosis from initial diagnosis and may help upfront TKI selection. Further follow-up analysis is ongoing to evaluate the effect of TKI therapy on longitudinal kinetics of mutations in serially collected samples. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Prognostic Impact of HMGCLL1 Gene Variant on Treatment Outcomes in Chronic Myeloid Leukemia (CML) Patients: Adverse Impact on the Response, Failure, and Progression with Imatinib Which Can be Abrogated By the Use of 2nd Generation Tyrosine Kinase Inhibitor (TKI) Upfront Therapy

BackgroundHMGCLL1 is characterized as a lyase activity enzyme located in the extramitochondrial region. Its biological and physiological role is not fully elucidated. Our previous study (Leukemia 2019) demonstrated that: 1) The HMGCLL1 gene variant, ACGTAATG haplotype (A-haplotype) is associated with increased expression of overall levels and isoform 3 (IS3) of the HMGCLL1 gene and predicts a decreased likelihood of deep molecular response after Imatinib (IM) therapy, 2) blockade of HMGCLL1 IS3 results in G0/G1 cell cycle arrest, leading to increased eradication of CML cell lines and CML leukemic stem cells, 3) blockade of HMGCLL1 isoform 3 significantly suppressed CD34+ fractions in CML patients (pts). It was unclear whether a second-generation tyrosine kinase inhibitor (2G-TKI) can reverse the adverse impact of the HMGCLL1 gene variant in CML pts. The present study assessed the prognostic impact of the HMGCLL1 gene variant in CML pts treated with IM or 2G-TKI, and its impact on treatment-free remission (TFR) after TKI discontinuation. Patients and methods Samples from 387 pts were sequenced. Group 1 included 252 pts from 2 centers whose samples were archived retrospectively. These pts were treated with IM (n=190, 75.3%) or second-generation TKIs (n=62) including Dasatinib (n=15, 6.0%), Nilotinib (n=37, 14, 7%), and Bosutinib (n=10; 4.0%). Group 2 included 135 patient samples from 4 countries that attempted to discontinue TKI for TFR. We applied our internal CML-specific smMIP panel with 332 amplicon probes including 8 HMGCLL1 SNPs (rs10948926, rs10948927, rs9370435, rs4546489, rs4275061, rs9475323, rs9475327, rs9296791). Linkage disequilibrium (LD) was assessed using Haploview software (Bioinformatics 2005). For Group 1, treatment outcomes were evaluated concerning major molecular response (MMR), molecular response (MR) with 2 log/deeper (MR2) or 4 log/deeper (MR4), failure-free survival (FFS), progression, and overall survival (OS). Disease characteristics and treatment outcomes were evaluated and compared according to the HMGCLL1 variants using a dominant model. For Group 2, molecular relapse-free survival (RFS) was calculated from the date of TKI discontinuation to the date of confirmed loss of molecular response (either loss of major MMR or two consecutive episodes of MR loss). Kaplan-Meier survival estimate was used to evaluate RFS and Cox's proportional hazard regression model was applied using the dominant model. Results HMGCLL1genotype and haplotype As shown in Fig A, the LD plot showed no recombination among the 8 SNPs, leading to one block for the 8 SNPs to construct a haplotype. Two haplotypes were constructed as CTCAGGCA (C-) or ACGTAATG (A-haplotype) with MAF of 0.674:0.279 in Group 1, and 0.703:0.216 in Group 2, respectively. Summary of outcomes in table 1. Treatment outcomes following TKI therapy according to the HMGCLL1 haplotype Homozygous A-haplotype (A/A) was associated with worse outcomes, showing a lower MR2 (65.9% vs 78.9% at 12 months, p=0.012), lower MMR (64.4% vs 86.8% at 3 years, p=0.00029), lower MR4 (34.7% vs 62.3% at 5 years, p=0.0001; worse FFS (62.8% vs 77.3% at 3 years, p=0.0014), higher risk of progression (16.2% vs 3.4% at 5 years, p=0.000678), and worse OS (56.1% vs 77.7% at 10 years, p=0.0021). The adverse impact of A/A-haplotype was more prominent in the pts treated with Imatinib: A/A-haplotype pts showed a 30-50% lower chance of MR2, MMR, and MR4 achievement, and 2-3 times higher risk of TFR and progression in comparison to those having C-haplotype when treated with Imatinib. However, the use of 2G-TKIs could abrogate the adverse impact of the A/A-haplotype. Impact of HMGCLL1 variant on treatment-free remission following TKI discontinuation While the 12-month RFS rate was 59.9% in overall pts (n=135), an inferior 12-month RFS rate was noted in A/A haplotype (43.8% vs 62.3%) but with borderline significance (p=0.116). Conclusion: The present study demonstrated that the HMGCLL1 gene variant is confirmed as predictive of CML outcomes. Moreover, our result suggests that the adverse impact of the HMGCLL1 genotype can be abrogated by using 2G-TKIs as upfront therapy. We aim to validate this data in a larger cohort of pts treated with 2G-TKI therapy to reach a clearer conclusion on this result. HMGCLL1 genotype information would be helpful to guide CML therapy given that pts with adverse HMGCLL1 genotypes could benefit from 2G-TKI therapy as front-line therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Is the 2nd Generation Tyrosine Kinase-Inhibitor a Better Initial Therapy Than Imatinib in Persons with Chronic Myeloid Leukemia Presenting in Accelerated Phase: A Multicenter Retrospective Study

Objectives Compare the treatment responses and outcomes between persons with chronic myeloid leukemia (CML) presenting in accelerated phase receiving a 2nd-generation tyrosine kinase inhibitor (2G-TKI) and imatinib as initial therapy. Methods Data from 442 consecutive subjects with CML presenting in accelerated phase according to the European LeukemiaNet (ELN) 2020 criteria from 32 centers were retrospectively collected. Propensity score matching (PSM) was performed to adjust for differences in baseline co-variates between subjects receiving a 2G-TKI or imatinib as initial therapy. Cumulative incidences of CCyR, MMR and MR4.5 were calculated using the Fine-Gray model. Transformation was defined as blood or bone marrow blasts ≥ 30% during TKI-therapy. Transformation-free survival (TFS) and survival were calculated by the Kaplan-Meier model. Results 442 subjects with CML presenting in accelerated phase were reviewed, including 147 (33%) received 2G-TKI and 295 (67%) received imatinib as initial therapy. 270 (61%) were male, median age was 43 years (Interquartile range [IQR], 31-55 years), median follow-up was 28 months (IQR, 13 - 53 months) in the 2G-TKI cohort and 51 months (IQR, 25 - 94 months) in the imatinib cohort reflecting the later availability of 2G-TKIs (p < 0.001), median treatment duration was 19 months (IQR, 9 - 41 months) in the 2G-TKI cohort and 32 months (IQR, 12 - 68 months) in the imatinib cohort (p < 0.001). 28 (26%) receiving 2G-TKI and 100 (34%) subjects receiving imatinib switched to another TKI during treatment. 379 subjects were identified by a 2:1 propensity-score matching in the 2G-TKI (n = 139; 37%) and imatinib (n = 240; 63%) cohorts. In the 2G-TKI and imatinib cohorts, the cumulative incidence of 2-year CCyR was 87% (95% Confidential Interval [CI], 86%, 87%) vs. 84% (84%, 84%, p < 0.001); MMR, 83% (82%, 83%) vs. 65% (65%, 65%, p < 0.001); MR4.5, 43% (42%, 44%) vs. 29% (28%, 29%, p = 0.006) when switching to another TKI, a transplantation and death were considered as competing events. When switching to another TKI was not considered as a competing event, cumulative incidences of 2-year CCyR were 91% (91%, 92%) vs. 83% (83%, 83%, p < 0.001); MMR, 80% (80%, 81%) vs. 66% (66%, 66%, p = 0.002); MR4.5, 40% (40%, 41%) vs. 28% (27%, 28%, p = 0.005) in the 2G-TKI and imatinib cohorts. The 2-year probabilities of TFS were 88% (81%, 94%) vs. 92% (88%, 96%, p = 0.116); survival, 97% (94%, 100%) vs. 98% (96%, 100%, p = 0.530) in the 2G-TKI and imatinib cohorts when censored at switching to another TKI, a transplantation or at last follow-up. Similarly, 2-year probabilities of TFS were 94% (89%, 98%) vs. 93% (90%, 96%, p = 0.868); survival, 97% (94%, 100%) vs. 96% (93%, 98%, p = 0.562) in the 2G-TKI and imatinib cohorts when censored at a transplantation or at last follow-up. Conclusions Persons with CML presenting in accelerated phase receiving a 2G-TKI as initial therapy achieved higher cumulative incidences of MMR and MR4.5 than those receiving imatinib, but similar TFS and survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Therapy in Patients with Chronic Myeloid Leukemia Outside of Clinical Trials: Results of the German CML-Registry (CML-VI)

Introduction: Tyrosine kinase inhibitors (TKI) have significantly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase (CP). With the introduction of 2nd and 3rd generation TKI, the options in the management of CML have increased. In clinical trials, 25%-50% of patients do not remain on initial treatment due to intolerance or inefficacy. Information outside of clinical trials is limited. Aim: The aim of this study is to analyze the use of different TKI in first-line treatment and the frequency of TKI switches in CML in real world. Methods: Patients with newly diagnosed CML between 1.1.2013 and 31.12.2019 were registered and followed annually up to 31.12.2021. Primary endpoint was the time to and reason for switching of any first-line treatment including treatment free remission (TFR)attempt. Further endpoints were progression-free survival (PFS), overall survival (OS), cytogenetic and molecular response. Analyses were performed using Kaplan-Meier estimates with SPSS. Results: 540 adult patients have been registered from 91 centers, 512 were evaluable. 281 patients (55%), were treated by resident oncologists, 231 patients (45%) in hospitals including 82 patients (16%) in university hospitals. 271 patients (53%) were male. At diagnosis, median age was 59 (range 16-100) years. The median follow-up was 67 (3-108) months. Information on first-line TKI treatment was available for 480 patients: 203 patients (42%) were treated with imatinib, 137 (29%) with nilotinib and 140 (29%) with dasatinib. TKI switch was reported in 155 cases (31%) after a median of 11 (0-68) months. Reasons for switching was failure in 49 patients (32%), intolerance in 88 patients (57%), and 18 patients (11%) switched TKI because of other reasons (study inclusion, desire to have children, patient request, unknown). 33 patients (7%) switched TKI more than once. 13 (8,4%) of the 155 patients with TKI-switch died during follow-up, whereas only 16 of 325 (4,9%) patients without TKI-switch. OS of patients with TKI-switch was 90%, of patients without TKI-switch 94% after 6 years. TKI stop for more than one month has been reported in 118 patients (24%) due to different reasons (attempt for TFR, intolerance, patient wish, pregnancy). 61 patients (12%) started a TFR attempt after a median of 46 (10-96) months of TKI treatment. Discontinuation criteria were not always met. Only 10 patients (6,5%) with TKI-switch started a TFR attempt compared to 51 patients (16%) who had only been treated with one TKI. 501 patients were in CP at diagnosis, 11 patients in accelerated phase (AP) and 2 patients in blast crisis (BC). Progression occurred in 9 patients (BC n=6, AP n=3) after a median time of 12 (9-22) months. Overall, AP and BC were diagnosed in 22 patients (2,3%). Of the total cohort, 29 patients died, OS was 93% after 6 years. An evaluable cytogenetic examination was carried out in 291 patients (57%) at diagnosis or in the course of disease. No statements can be made about achieving of complete cytogenetic remission as follow up results were only available in 15% and monitoring was carried out using RQ-PCR in most patients. A major molecular response (MMR, BCR::ABL1 <0.1%) was reached by 422 patients (85%), a deep molecular response (defined as BCR::ABL1 ≤0.01) by 365 patients (74%) within the follow-up period. Cumulative incidence calculation and study of patients who lost their MMR are ongoing. There is no information about the molecular status of 18 patients. Conclusion: Results of the CML VI-registry provided information on treatment but also on baseline characteristics and diagnostic parameters of CML patients in real world. The median age of the patients at diagnosis was higher than in other clinical trials. In routine care, data demonstrated high switching rates of first-line treatment and frequent TFR attempts without meeting the guideline criteria. OS rates were as high as in clinical trials and confirm normal life expectation of CML patients. MMR was reached in 85% and DMR in 74% in this population. Progression is rare. In conclusion, the CML-registry offers importing data confirming a good outcome of response and survival for CML patients outside of clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Background: Older patients with ALL fare poorly with conventional chemotherapy. Patients aged 55-65 on E2993 and ≥ 60 treated with Hyper-CVAD have 5-year overall survival (OS) of just 21% and 20%, respectively (Sive. BJH. 2012 and O'Brien. Cancer. 2008). Recently, HyperCVD with inotuzumab +/- blinatumomab in patients ≥ 60 years old with Ph- B ALL demonstrated an improved 5-year OS of 47% with 38% of patients dying in remission (Short. Blood. 2021). AlloBMT provides an alternative consolidation strategy. Registry studies in ALL patients ≥ 60 years old and B ALL patients ≥ 55 years old who underwent alloBMT with RIC in CR1 demonstrated 5 and 3-year OS of 42% and 45%, respectively (Roth-Guepin. Oncotarget. 2017 and Rosko. Am J Hematol. 2017). These studies utilized heterogenous conditioning and graft-versus-host disease (GVHD) prophylaxis regimens. The use of high-dose post-transplantation cyclophosphamide as GVHD prophylaxis facilitates transplants in older adults with low rates of non-relapse mortality, GVHD, and the use of HLA haploidentical donors (Kasamon. JCO. 2015). Methods: The bone marrow transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received a first alloBMT using PTCy from January 2008-January 2021. Characteristics of patients were summarized and compared using Fisher's exact test for categorical variables. Estimators of OS and relapse-free survival (RFS) were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model, or Fine and Gray's model for cumulative incidence of relapse (CIR)/nonrelapse mortality (NRM) considering competing risks. Results: A total of 77 patients aged ≥ 55 underwent a first alloBMT with PTCy for ALL. The vast majority were performed in CR1 (85.7%), utilized RIC (88.3%), and were performed for B ALL (90.9%). Demographics and transplant characteristics are presented in Table 1. RIC consisted of fludarabine, cyclophosphamide and total body irradiation followed by PTCy-based GVHD prophylaxis as previously described (Kasamon. BBMT. 2008). Relapse-free survival (RFS) and OS at 5 years for the entire cohort were 46% (95% CI 34-57) and 49% (95% CI 37-60), respectively, with a 5-year CIR of 27% (95% CI 18-38) and NRM of 28% (95% CI 18-39). The cumulative incidences of grade 3-4 acute GVHD at 1 year and chronic GVHD at 3 years were 3% (95% CI, 0% to 9%) and 13% (95% CI 5% to 21%), respectively. In univariate analysis, the use of myeloablative conditioning led to worse RFS (HR 0.25, p=0.0004); while the absence of MRD (HR 2.93, p=0.008), transplant in CR1 (HR 3.81, p=0.0004), and transplant for Ph+ ALL vs. T ALL (HR 3.15, p=0.03) led to improved RFS. Subsequent analysis focusing on the 54 patients receiving RIC alloBMT in CR1 for B ALL demonstrated RFS and OS at 5 years of 61% (95% CI 46-73) and 64% (95% CI 49-76), respectively, (see Figure 1) with a 5-year CIR of 16% (95% CI 7-27) and NRM 24% (95% CI 13-36), although just 7% at 1 year. For B ALL patients transplanted with RIC in CR1, 3-year NRM was higher among patients who received a peripheral blood stem cell transplant (55%, 95% CI 18% to 81%), those treated with rituximab pre-transplant (36%, 95% CI 16% to 57%), and those who received ≥100 mg/m2 of doxorubicin equivalent for ALL (67%, 95% CI 19% to 90%). Outcomes did not differ among the 20% of patients who received pre-transplant blinatumomab compared to those who did not. Among the 23 Ph+ B ALL patients transplanted with RIC in CR1 following treatment with a 2nd or 3rd generation tyrosine kinase inhibitor (TKI), the 5-year CIR was 5% (95% CI, 0% to 22%). Conclusions: RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Generic Dasatinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia with Reference to Early Molecular Response: Results from a Single-Center, Randomized Controlled Study from India

Background: Chronic myeloid leukemia (CML) is the commonest leukemia in adult population in India. The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 fusion transcript in CML has dramatically improved survival of CML patients. Generic formulations of imatinib mesylate have been the mainstay of TKI therapy in Indian CML patients for more than a decade, due to prohibitive costs of 2nd generation TKIs and poor socio-economic status of majority of patients. However, with the availability of generic dasatinib in India since March 2021, the cost of dasatinib therapy has become comparable to that of generic imatinib treatment, thereby enabling more extensive use of dasatinib as first-line TKI therapy in CML patients in India. Achievement of early molecular response (EMR) after 3 months of first-line TKI therapy, defined as blood BCR-ABL1 transcript level ≤ 10% [international scale (IS)], has emerged as an important predictor of favorable long-term outcome in CML-CP. There is scarcity of data on efficacy & safety of generic formulations of dasatinib vis-à-vis generic imatinib in CML-CP patients in India, which the present study has attempted to explore at a tertiary care hospital in India. Objectives: The objectives of the study were to compare early molecular response (EMR) [defined as BCR-ABL1 transcript level ≤ 10%, I.S.] at 3 months of therapy with generic dasatinib versus generic imatinib in newly diagnosed CML-CP patients and to compare treatment-related adverse effects in the two groups. Methods: This randomized controlled study enrolled newly diagnosed CML-CP patients after obtaining institutional ethics committee approval & informed consent. Inclusion Criteria:Newly diagnosed patients with chronic phase CML.Age ≥ 12 years. Exclusion Criteria:Patients with de novo accelerated phase or blast phase CML.Pregnancy & lactation.Patients with pre-existing pleural effusion, grade ≥ 3 lung disease, or pulmonary arterial hypertension.Patients with angina, or grade ≥ 3 cardiac disease [as defined by the New York Heart Association (NYHA) criteria] at diagnosis.Patients with prolonged QTc interval (> 480 msec) at baseline. The EUTOS long-term survival (ELTS) risk score was calculated at diagnosis. Patients were randomized to one of the two following treatment groups: Group A: Dasatinib 100 mg p.o. once daily (60 mg/m2/day for age <18 years). Group B: Imatinib 400 mg p.o. once daily (340 mg/m2/day for age < 18 years). Follow up & monitoring of patients was done every 2 weekly till completion of 3 months of TKI therapy, followed by assessment of hematological response & molecular response as per standard criteria. Results: A total of 61 consecutive CML patients were screened between June 2021 and March 2022, out of which 54 patients with confirmed diagnosis of CML-CP were enrolled in the study and were randomized to receive generic dasatinib or generic imatinib as first-line therapy and were followed up for 3 months for EMR and complete hematological response (CHR). Four patients were lost to follow up and data was analyzed for 50 patients for whom EMR results at 3 months was available. Out of these 50 patients, 24 patients received dasatinib & 26 patients received imatinib. The median age of patients was 33 years (range 18-64 years), with male: female ratio of 1.3: 1. Achievement of CHR was documented in 96% of patients in both dasatinib & imatinib treatment arms. EMR at 3 months was achieved in overall 72% patients in study [19/24 patients (79%) in dasatinib arm & 17/26 patients (65%) in imatinib arm]. However, the difference was not statistically significant (p = 0.27). Notably, EMR rates in ELTS intermediate-risk group was 86% in dasatinib arm versus 42% in imatinib arm, and EMR rates in ELTS high-risk group was 82% in dasatinib arm versus 57% in imatinib arm (p = 0.33). The incidence of grade 3-4 adverse events was not significantly different in the two treatment groups. The patient characteristics & treatment results are summarized in Table 1 & Figure 1. Conclusion: The results of the present study suggested that generic formulations of dasatinib were well-tolerated and were associated with improved early molecular response rates compared to generic imatinib in CML-CP patients in India. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML Resistant to 2nd-Generation TKIs: Mechanisms, Next Steps, and New Directions.

The clinical scenario for chronic myeloid leukemia patients rapidly changed after the introduction of tyrosine kinase inhibitors (TKIs). Second-generation TKIs as frontline treatment increased the rate of deep molecular responses without increasing the rate of overall survival. About 20% of patients experience resistance to these agents, needing alternative treatments. Here, we reviewed the possible mechanisms of resistance, available treatment, and new drugs developed to counteract and overcome resistance. Results of novel TKIs have been recently reported, especially for the setting of T315I mutated patients, such as olverembatinib and asciminib, or for patients who developed resistance due to other mutations, such as vodobatinib. Most of new TKIs are selected among compounds tested selective on ABL, therefore without possible off-target effects in the long term. New potential treatments are on the horizon in the field of CML, able to rescue patients treated firstly with one or more second-generation TKIs. Results of ongoing trials and real-world evidence dataset will help us to identify the appropriate timing of intervention and to select appropriate candidate to these drugs.

LBA58 Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung cancer (EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: Second interim analysis of phase III ORIENT-31 study

The randomized, double-blind, phase 3 ORIENT-31 study was to evaluate sintilimab (sin, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo), vs chemo, in patients (pts) with EGFRm nsqNSCLC who progressed on EGFR TKIs therapy. The first interim analysis (IA) showed sin + IBI305 + chemo significantly improved progression-free survival (PFS) vs chemo alone (Lu, et al. Lancet Oncol 2022). Eligible pts were randomized (1:1:1 at the first stage and 2:2:1 at the second stage) into Arm A (sin + IBI305 + chemo), Arm B (sin + placebo [pb] 2 + chemo) and Arm C (pb1 + pb2 + chemo). Sin/pb1 (200 mg), IBI305/pb2 (15 mg/kg), pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sin/pb1, IBI305/pb2 and pemetrexed. The primary endpoint was PFS assessed by IRRC per RECIST v1.1. Per prespecified statistical analysis plan, the second IA (reported here) aimed to evaluate the PFS between Arm B and Arm C, and the superiority conclusion of Arm A over Arm C has been achieved at the first IA. By data cutoff (Mar 31, 2022), 476 pts were randomized (Arm A/B/C: 158/158/160). Median age was 57.0 years. 37.0% pts had brain metastasis. Previously, 63.0% pts received 1st or 2nd generation (G) TKI with T790M-, 26.3% pts received 1st or 2nd and then 3rd G TKI with T790M+, and 10.5% pts received first-line 3rd G TKI. With a median follow-up of 13.1 months, median PFS (95% CI) by IRRC was 7.2 months (6.6, 9.3) in Arm A, 5.5 months (4.5, 6.1) in Arm B, and 4.3 months (4.1, 5.3) in Arm C. PFS was significantly improved in Arm B vs Arm C (HR 0.723, 95% CI: 0.552, 0.948; P=0.0181). Confirmed ORR by IRRC was 48.1%, 34.8% and 29.4% in Arm A, B and C respectively; DCR was 86.1%, 81.6% vs 75.6%; median DOR was 8.5 months, 7.4 months vs 5.7 months. Grade ≥3 treatment-emergent adverse events occurred in 59.5%, 46.2%, and 56.9% pts respectively. Sin combined with or without IBI305 and chemo significantly improved PFS in pts with advanced EGFRm nsqNSCLC who progressed on EGFR-TKI therapy, vs chemo alone.

Co-variates associated with outcomes of tyrosine kinase-inhibitor therapy in persons with chronic myeloid leukaemia initially presenting in accelerated phase

We interrogated data from 278 consecutive subjects with chronic myeloid leukaemia (CML) presenting in accelerated phase diagnosed by European LeukemiaNet(ELN) criteria receiving initial imatinib (n = 187) or a 2nd-generation tyrosine kinase-inhibitor (2G-TKI; n = 91). In multi-variable analyses, blood and/or bone marrow blasts ≥15% (Hazard ratio [HR] = 3.7 [1.6, 8.5], p = 0.003) and blood basophils <3% (HR = 4.6 [2.0, 10.7], p < 0.001) were significantly-associated with worse transformation-free survival (TFS). Age ≥60 years (HR = 4.3 [1.7, 11.4], p = 0.003), platelet concentration <230 × 10E + 9/L (HR = 4.7 [2.0, 10.7], p < 0.001) and blood and/or bone marrow blasts ≥9% (HR = 3.9 [1.7, 8.7], p = 0.001) were significantly-associated with worse survival. Based on number of adverse prognostic co-variates of TFS and survival, respectively, subjects were classified into the low- (none), intermediate- (one) and high-risk (≥2) cohorts with significant difference in TFS and survival (all p < 0.001). In propensity-score matching analysis subjects initially receiving a 2G-TKI had higher cumulative incidences of cytogenetic and molecular responses but similar TFS and survival to those receiving imatinib. Our data should help inform physicians treating person with CML initially presenting in accelerated phase.

Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability.

Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts’ secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations.

Triple positive lung cancer: A case report

Background: Targeted therapies in nonsmall cell lung cancer has changed the landscape of management and carved the disease in to more different sub types. Despite of considerable initial response to 1st generation and 2nd generation tyrosine kinase inhibitors patients develop resistance in the due course. Secondary mutations are due to threonine and methionine substitution at 790 (T790M) of EGFR. T790M mutation are resistant to 1st and 2nd generation TKI.Osimertinib is a irreversible third generation epidermal growth factor receptor tyrosine kinase inhibitor effective against EGFR T790M mutation positive lung cancer. Patients are inescapable of developing resistance with Osimertinib in spite of initial response and leaving no further definite therapeutic options. In 20-30% patients with osimertinib resistance develop EGFR C797S mutation. Our objective is to show the patient journey with primary, secondary mutation withT790M and tertiary mutation in C797S. Key Messages: Prospective molecular tumor profiling is now the standard of care in the treatment of metastatic NSCLC. Re-biopsy or liquid biopsy on progression of first and second line TKI to look for T790M has already been in routine practice. Re-biopsy or liquid biopsy on progression of third line TKI and molecular profiling can guide us in further management.

Adverse outcomes in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Follow-up of patients diagnosed 2002-2017 in a complete coverage and nationwide agnostic register study.

Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort‐study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002–2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near‐complete nationwide coverage were utilized for data acquisition. Median follow‐up was 6 (IQR, 3–10) years with a total follow‐up of 8510 person‐years for the full cohort. Among 670 analyzed disease categories, the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5–2.6), heart failure 2.6 (2.2–3.2), pneumonia 2.8 (2.3–3.5), and unspecified sepsis 3.5 (2.6–4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within‐cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5–5.6) and chronic ischemic heart disease (2.2; 1.2–3.9), dasatinib for pleural effusion (11.6; 7.6–17.7) and infectious complications, for example, acute upper respiratory infections (3.0; 1.4–6.0). Our extensive real‐world data reveal significant risk increases of severe morbidity in TKI‐treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored.

TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy-EGFR mutated non-small cell lung cancer IV patients treated with osimertinib.

BackgroundThe negative prognostic and predictive value of TP53 co-mutations (TP53 mt+) in EGFR mutated (EGFR mt+) non-small cell lung cancer (NSCLC) is increasingly being acknowledged. Data consistently show that TP53 mt+ impact negatively on 1st line objective response rate (ORR), progression free survival (PFS) and overall survival (OS) with 1st and 2nd generation tyrosine kinase inhibitors (TKI). However, a negative predictive impact has not been shown for the 3rd generation TKI Osimertinib. Therefore, we investigated the impact of TP53 mt+ in EGFR mt+ NSCLC carrying a T790M resistance mutation and treated in 2nd/further lines with Osimertinib.MethodsA total of 77 EGFR mt+ NSCLC IV patients carrying a T790M resistance mutation from two institutions were analyzed for TP53 mt+. Clinical data including sex, age, presence of CNS metastases, etc., as well as types of EGFR and TP53 mt+ were captured. PFS and OS were calculated from the start of Osimertinib.ResultsTP53 mt+ were found in 32/77 patients (42%). TP53 mt+ was a statistically significant independent negative predictive factor for PFS and OS. PFS for TP53 mt+ patients were 9 months vs. 14 months for patients with TP53 wild-type (TP53WT) (P<0.008). OS for TP53 mt+ patients was 16 months vs. 24 months patients with TP53WT (P<0.025).ConclusionsTP53 mt+ have a negative impact on PFS and OS in a group of patients carrying a sensitizing EGFR mt+ and a T790M resistance mutation treated with Osimertinib. These data, together with the data for 1st/2nd generation TKI in 1st line treatment call for additional therapeutic and management concepts for this subgroup of patients.

Real world outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation–A single institution experience

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph+ ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph+ ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p = 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (25/40) and any grade chronic GVHD was 77.5% (31/40). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p = 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p=0.0198) but did not significantly change 2-year OS (p = 1). Patients receiving 1st and 2nd generation TKIs pre- and post-HSCT seem to have favorable outcomes, although type of TKI (pre-HSCT) did not significantly impact EFS or OS. In addition, attaining a CMR pre-transplant improved EFS, but did not change OS.

Second-Generation Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response: A Systematic Review and a Meta-Analysis.

The treatment with 2nd-generation tyrosine kinase inhibitors (2G-TKIs), namely, dasatinib and nilotinib, has been reported to have faster and deeper responses in newly diagnosed chronic phase-chronic myeloid leukemia (CP-CML) patients as compared with imatinab. A number of studies on the discontinuation of 2G-TKIs have been conducted and recently published. A meta-analysis was conducted in this study to assess the rate of treatment-free remission (TFR) rate as well as the long-term safety of 2G-TKI discontinuation in CML patients with stable deep molecular response (DMR). 517 patients were recruited in 5 single-armed, prospective cohort studies. The overall weighted mean TFR rate at the follow-up of 12 months reached 57% (95% CI 51-64%; I2 = 56.4%). The weighted mean TFR rate at the 24-month follow-up was 53% (95% CI 47-60%; I2 = 47.1%). The loss of TFR was primarily concentrated in the first 12 months. 96.5% of patients, having restarted TKI therapy after a molecular relapse, achieved major molecular response (MMR) rapidly. There were four deaths at the two-year follow-up. As suggested from the results of the final study, 2G-TKI discontinuation in CML patients with stable DMR was reported to be feasible. Relapsed patients were retreated with 2G-TKI, and over 95% of patients could reach MMR. Almost no deaths occurred due to adverse events in two years after discontinuation, and more than half of the patients could maintain a TFR.