Achievement Of Major Molecular Response Research Articles

Current Status and Management of Chronic Myeloid Leukemia in the Gulf Region: Survey Results and Expert Opinion.

Studies on chronic myeloid leukemia (CML) in the Gulf region are scarce, consisting of a survey and expert meeting that included 15 experts in 2023 which discussed CML diagnosis, testing, treatment objectives, toxicities, and discontinuation in the Gulf region. Most patients were reported to be in first-line therapy, and the most common treatments were imatinib/imatinib generic in first-line and dasatinib in second- and third-lines. Mutation analysis was not reported to be routinely performed at the time of diagnosis but rather in case of progression to accelerated/blast phase or any sign of loss of response. While all participants were aware that BCR-ABL should be monitored every three months during the first year of treatment, 10% reported monitoring BCR-ABL every six months in practice due to test cost and lab capability. The most important first-line therapy objective was "achievement of major molecular response" (MMR) in younger patients and "overall survival" in older ones. The most important treatment objectives were "MMR" and "early molecular response followed by prolongation of overall survival" in the short term and "treatment-free remission" in the long term. The current practices in CML in the Gulf region appear to be similar to global figures.

Peripheral blood quantitation of CD26 positive leukemic stem cells as a predictor of tyrosine kinase inhibitor response in chronic myeloid leukemia.

Leukemic stem cells (LSCs) are the transcriptionally low/silent cells which are resistant to the tyrosine kinase inhibitor. These have been found to play a pivotal role in disease relapse in chronic myeloid leukemia (CML) cases. The present study evaluated the correlation of absolute CML-LSC count in the peripheral blood (PB) at diagnosis and achievement of major molecular response (MMR) at 12 months in patients of CML-CP. This was a prospective, observational, non-interventional single center study including newly diagnosed adult (>18 yrs) CML-CP patients. Absolute CD26 + CML-LSC quantification was done by multiparametric flow cytometry. Patients were treated with Imatinib treatment and subsequently monitored at 3-month intervals for BCR::ABL transcript levels. MMR was defined as a BCR::ABL1 transcript level of less than 0.1% on international scale. A total of 89 patients were enrolled in the study out of which 40.5% achieved MMR at 12 months. There was a significant difference in the median absolute CML-LSC count of the patients who achieved MMR at 12 months as compared to those who did not (58.5 vs 368.1 cells/μL; p value <0.001). Using a ROC analysis, a count of <165.69 CML LSC/μL was identified to have a sensitivity of 83.8% and specificity of 72.4%, in predicting the MMR at 12 months. Absolute CML-LSC count at diagnosis in the PB predicts the MMR achievement at 12 months. An absolute count of less than 165 cells/μL is highly predictive of achieving MMR at 12 months.

Improvement of Treatment-Free Remission Rate Following Discontinuation of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Phase, Chronic Myeloid Leukemia

Backgrounds: Several studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive sufficient tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. The main factors affecting Treatment free remission (TFR) are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment. Aims: To investigate impact of longer duration of DMR, we analyzed the outcome of patients with CP-CML who maintained DMR for more than 6 years during TKIs treatment and discontinued TKIs. The clinical and molecular immunological application criteria were also investigated for safer and more successful TFR. Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. After discontinuation, molecular responses were monitored for up to six months per month, up to 12 months every two months, and every three months thereafter using the qRT-PCR method. In the case of relapse, defined as loss of major molecular response (MMR), the last TKI therapy was reintroduced and molecular responses after resumption were monitored monthly until achievement of MMR using qRT-PCR. Results: Altogether 116 patients (50 males and 66 females) discontinued TKI. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. Prior to discontinuation, all patients received TKIs for a median of 120.6 months (range, 113.9-127.3), and the duration of sustained MR4.5 was 75.0 months (range, 70.7-79.3). At the time of discontinuation, 93 patients (80.2%) were receiving their first TKI (70 imatinib, 13 nilotinib, 6 radotinib, and 4 dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. After a median follow-up from treatment discontinuation of 42.2 months (range, 35.3-49.1), 28 (24.1%) patients have lost their response at a median of 8.4 months (range, 4.9-11.9) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation and 7 (25.0%) patients lost MMR after 12 months from discontinuation. TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) re-achieved MMR with a median of 5.6 months (range, 4.0-7.2). By univariate analysis, a TKI treatment duration of 10 years or more was the only significant predictor for maintained response (P&amp;lt;0.048). Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.

Efficacy of Frontline Treatment with Initial Low-Dose Tyrosine-Kinase Inhibitors in Elderly Patients with Chronic Myeloid Leukemia: A “Campus CML” Study

Introduction Three TKIs, imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based mainly on evaluation of patient's characteristics and clinical expectations. To avoid long term adverse events or potential drug interactions, elderly patients may start CML treatment with a frontline reduced dose of TKI (RD-TKI). Aim To analyse outcome of CP-CML patients aged over 65 years in a large and unselected cohort treated with RD-TKI. Methods We retrospectively evaluated 747 patients from 1/2012 to 12/2019 at 36 Hematology Centres participating at the “Campus CML” project. Results Clinical features for the whole cohort according to frontline TKI initial dose are reported in Table 1. Among all patients, 605 (81%) were treated with standard dose (SD) while the remaining 142 (19%) with reduced dose (RD). As to frontline TKI, 579 patients (77%) received IM and 158 (23%) a 2G-TKI (DAS n=78, 49%; NIL n=80, 51%). Of the 142 RD-TKI, 122 (85.9%) started with IM, 14 (9.9%) with DAS and 6 (4.2%) with NIL. Median RD was 100 mg for IM (range 100-300), 20 mg for DAS (range 20-50) and 250 mg for NIL (range 150-300). RD-TKI was mainly reported in IM treated patients (p=0.018), in elderly (p&amp;lt;0.001) and in patients with comorbidities, in particular diabetes (p=0.005) and ischemic heart disease (p=0.039). Number of concomitant drugs was also significantly associated with RD-TKI (p&amp;lt;0.001) probably to avoid drug interactions and subsequent toxicity. In detail, among RD-TKI, 41.1% of patients was treated with more than five concomitant drugs. Sokal score did not impact on TKI starting dose. No differences emerged between SD-TKI and RD-TKI in terms of haematological or extra-haematological toxicity. TKI frontline dose was not associated with difference in resistance, nor primary neither secondary resistance. Progression to blastic phase was reported in 1.2% of the whole population, none of which in RD-TKI. At 12 months no differences were noted in terms of achievement of major molecular response (MMR), obtained in 22.4% of SD-TKI treated patients and in 19% of RD-TKI treated patients. RD-TKI had inferior probability of deep molecular response (DMR) achievement (p=0.003), reported in 12.6% of patients. No differences were reported in 12-months cumulative rate of permanent discontinuation for any cause and for primary resistance between SD-TKI and RD-TKI as reported in Figure 1. Conclusions RD-TKI was a frontline treatment strategy used mainly in frail elderly patients, with more comorbidities and concomitant therapies. RD-TKI did not impact on primary resistance leading to TKI switch. While no differences were reported in the rate of MMR, the rate of 12-months DMR achievement was inferior in RD-TKI, but this result need to be confirmed with longer follow-up.

Flumatinib for the Treatment of Adult Patients with Resistant or Intolerant Chronic-Phase Chronic Myeloid Leukemia: Results from Real-World Data

Introduction Over the past decades, BCR-ABL1 tyrosine kinase inhibitors (TKIs) as the initial treatment for chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML-CP) have dramatically turned CML-CP into a manageable and potentially curable chronic disease. Nonetheless, in spite of the massive improvement in CML treatment over the last years with the introduction of TKIs, some patients (20%-30%) display intrinsic or acquired resistance to treatment during the disease course. Flumatinib Mesylate is a newer and orally available TKI with higher selectivity and potency against BCR-ABL1 kinase versus imatinib. According to the previous data，flumatinib can be an effective first-line treatment for CML-CP. Patients and Methods This study was initiated mainly to observe the safety and efficacy of flumatinib in the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia, especially in second-line or above treatment in the real world. Efficacy and safety assessments were collected for the intent-to-treat population. Major molecular response (MMR) was defined as BCR-ABL1 transcript level ≤ 0.1% on the International Scale (IS), molecular response (MR4) was defined as BCR-ABL1 transcript level (IS) ≤ 0.01%; MR4.5 was defined as a BCR-ABL1 (IS) transcript level ≤ 0.0032%. DMR was defined as MR 4.0 or MR 4.5. Results Among the 58 evaluable patients with CML-CP, 54% were male, 47% were female. The median age of these patients is 45Y. During the observation period, there were 28 second-line conversion patients (48%), 19 third-line conversion patients (33%), and 11 fourth-line and above patients (19%). Prior therapies included imatinib, dasatinib, nilotinib, olverembatinib, radotinib and ponatinib. All patients converted to treatment of 600mg flumatinib daily. Among the 58 evaluable patients, 20 patients who had been treated with imatinib alone were converted to flumatinib, including 9 cases of IM resistance, 8 cases of IM intolerance and 2 case of personal reasons. During the 1-year follow-up, 52% of patients (n=30) were evaluable for the achievement of MMR. The patients with BCR-ABL1 (IS) &amp;gt; 10% at baseline, 3, 6 and 12 months were 48%, 17%, 23% and 26%, respectively; for patients with BCR-ABL1 (IS) &amp;lt; 0.1% were 26%, 40%, 49% and 52%, respectively; for patients with DMR were 26%, 40%, 49% and 52%, respectively. For imatinib-intolerant or -resistant patients, MMR was 44%. Subgroup analyses showed that the imatinib-intolerant or -resistant patients with BCR-ABL1 (IS) &amp;gt;10% at baseline, 3, 6 and 12 months were 65%, 0%, 10% and 0%, respectively; for patients with BCR-ABL1 (IS) &amp;lt; 0.1% were 10%, 33%, 80% and 44%, respectively; for patients with DMR were 5%, 11%, 30% and 11%, respectively. Meanwhile, 11% of patients could not be detected at molecular level (0.000%). Of the 58 patients, only Grade 1 AEs were reported, including diarrhea, rash and eye edema. Conclusion Flumatinib has good efficacy and safety in the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia, it will be a good choice for second-line or above treatment for CML-CP In clinical practice.

Cytokine profile in patients with chronic myeloid leukemia

Resistance to tyrosine kinase inhibitors (TKIs) is currently an important clinical problem in the management of patients with chronic myeloid leukemia (CML). Recent studies suggested that aberrant cytokine secretion may be among the BCR/ABL-independent mechanisms of resistance, thus contributing to the persistence of leukemic stem cells in spite of continuous targeted therapy. The aim of the study was to evaluate concentration of cytokines in the serum of patients with CML depending on the efficiency of therapy.Quantitative determination of the cytokines (TNFα, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IL-18, IFNα and VEGF) in blood serum of patients with chronic-phase CML (n = 84) and healthy subjects (n = 30) was performed using enzyme immunoassay (ELISA). The patients with CML were divided into 3 groups depending on the duration of therapy: group I, newly diagnosed patients (n = 10); group II, patients receiving therapy for &lt; 12 months (n = 10); group III included patients receiving therapy for more than 12 months (n = 64).The results of our study showed that cytokine concentration among CML patients significantly differed, depending on the duration of therapy. Significantly higher concentration of IL-17, IL-6, IL-1β, IL-10, IL-18, IL-2 and TNFα was found in group I compared with control group. Group II patients also demonstrated significantly higher concentrations of TNFα, IL-6, IL-10, IL-18 and IFNα by comparison with control group, as well as higher concentration of IFNα compared with in groups I and III. In group III, concentrations of IL-17, IL-1β, TNFα, IL-6, IL-10, IL-18 were significantly higher than in control group. When compared with group I, it was found that concentrations of IL-1β, IL-2 and IL-18 were significantly lower. A direct correlation was found between expression levels of chimeric BCR/ABL gene, (a marker of CML malignancy), and concentrations of IL-1β and IL-17. ROC-analysis demonstrated high-quality models which showed an association between achievement of major molecular response (MMR) and low serum concentrations of IL-1β, IL-6 and IL-17.Hence, the results of our study have shown that determination of IL-1β, IL-6 and IL-17 concentrations may be a prognostic marker for assessing the efficiency of therapy and probability of achieving MMR in CML.

Gene Expression Pattern of ESPL1, PTTG1 and PTTG1IP Can Potentially Predict Response to TKI First-Line Treatment of Patients with Newly Diagnosed CML.

The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off ≥ 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first = line treatment.

Роль цитокинов и регуляторных молекул клеточного цикла в прогнозировании достижения ответа на терапию у больных хроническим миелолейкозом

Introduction. Despite significant advances in therapy of patients with chronic myeloid leukemia (CML), improved survival rates, development of resistance to tyrosine kinase inhibitors (TKIs) remains an urgent problem. Aim. To study the correlation between the level of expression of regulatory proteins p53, c-myc, ki-67 and caspase-3 on the bone marrow cells and the concentration of certain pro- and anti-inflammatory cytokines in blood serum with the effectiveness of therapy in patients with CML. Materials and methods. Seventy-four CML patients with chronic phase of the disease receiving TKI therapy were examined. In all patients, the concentration of certain cytokines and growth factors (TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IL-18, IFN-α, and VEGF-A) was determined in blood serum by enzyme immunoassay and immunocytochemical study of bone marrow smears with monoclonal antibodies against antigens of regulatory molecules ki-67, p53, c-myc, and caspase-3. To determine the role of the biomarkers in predicting the therapy effectiveness, a comparative analysis of their values in groups of patients with a major molecular response (MMR) (n = 50) and without MMR (n = 24) was performed. Results. A comparative analysis of the expression of regulatory molecules on the bone marrow cells and the blood serum concentration of cytokines and growth factors of CML patients, depending on depth of the response to TKI therapy, showed that patients who did not achieve MMR had a significantly higher level of caspase-3 expression and concentration of pro-inflammatory cytokines IL-1β, IL-2, IL-6 and IL-17, as well as growth factor VEGF-A compared with those in patients with MMR. In turn, the achievement of MMR was characterized by a higher level of expression of regulatory molecules p53 and c-myc, as well as an increase in the IL-10 concentration and a decrease in the IL-1β, IL-2, IL-6 and IL-17 concentration. Analysis of the correlation between the level of expression of regulatory molecules and the single cytokine concentration showed a negative correlation between c-myc and p53 with IL-2, IL-1β, IL-17 and a positive (direct) correlation between c-myc and p53 with IL-10, a positive correlation between caspase-3 and IL-2, IL-1β, IL-6, IL-17 and a negative correlation between caspase-3 and IL-10. Thus, the achievement of MMR in patients with CML is more likely with a higher expression of regulatory molecules c-myc and p53 on the bone marrow cells, low expression of caspase-3, and low serum concentrations of IL-2, IL-1β, IL-17, IL-6 and a high concentration of IL-10, which indicates synergism of the biomarkers in the pathogenesis of CML and its tumor progression. The ROC analysis results showed the high quality of predictive models characterizing the achievement of MMR at the level of expression of c-myc &gt; 6%, p53 &gt; 4% in the bone marrow, which correlates with a low serum concentrations of IL-2, IL-1β, IL-17 and a high concentration of IL-10, and indicates the possibility of using these indicators as potential biomarkers of effectiveness of CML therapy and achievement of MMR. Conclusion. The results of the study showed that the concentration of cytokines in the blood serum of CML patients correlates with the intensity of expression of c-myc, p53 and caspase-3 proteins and is important in predicting the effectiveness of therapy.

Цитокиновый статус больных хроническим миелолейкозом

Introduction. Altered cytokine secretion has been described in many types of cancer. Being a key mediator of intercellular interactions, they can contribute to the development of resistance to targeted therapy and cytostatic drugs in chronic myeloid leukemia (CML). Aim. To evaluate the relationship between cytokine spectrum indicators in patients with CML and the effectiveness of targeted tyrosine kinase inhibitors (TKI) therapy. Materials and methods. Quantitative determination of the concentration of cytokines TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-18, IFN-α in blood serum of patients with CML (n = 60) and apparently healthy blood donors (n = 22) was carried out using enzyme-linked immunosorbent assay (ELISA). The phase of the disease and the depth of molecular response were determined according to criteria of the European Leukemia Net 2020. Stratification of CML patients by risk groups was carried out according to the Sokal (1984), EUTOS long-term survival (ELTS) (2016) scores. Hematological and non-hematological toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.5.0, 2017). Results. It was found that the serum concentration of a number of cytokines in the group of patients with CML was significantly higher compared to the control group: TNF-α – 2.80 and 0.70 pg/ml, p &lt; 0.001, IL-6 – 3.10 and 0.70 pg/ml, p &lt; 0.001, IL-18 – 296.40 and 122.10 pg/ml, p &lt; 0.001, IL-10 – 5.15 and 0.95 pg/ml, p &lt; 0.001, IFN-α – 5.60 and 4.00 pg/ml, p = 0.006, respectively. Among patients with CML, the level of cytokines varied depending on the level of molecular response and the type of TKI. Patients who did not achieve a major molecular response (MMR) were characterized by a significantly greater increase in the secretion of TNF-α, IL-6 and IL-1β (6.65 and 2.30 pg/ml, p = 0.004, 9.40 and 2.80 pg/ml, p &lt; 0.001, 3.69 and 0.88 pg/ml, p = 0.004, respectively) compared with patients with MMR. However, only IL-6 was a statistically significant prognostic factor influencing the achievement of MMR (odds ratio 1.131, confidence interval 1.015–1.260, p = 0.025). Among patients receiving imatinib therapy, the level of TNF-α was lower compared to patients receiving nilotinib, dasatinib and bozutinib (2.10, 4.00, 6.85 and 4.25 pg/ml, respectively, p = 0.013). Conclusion. The results of the research demonstrated increased secretion of TNF-α, IL-6, IL-18, IL-10, and IFN-α in CML patients, which may indicate an important role in the pathogenesis of CML. TNF-α, IL-6, and IL-1 levels were higher in patients who did not achieve MMR, and IL-6 was a statistically significant predictor the achievement of MMR.

Additional Mutational Events at Diagnosis of CML Confer Inferior Failure-Free Survival and Molecular Response for Patients Treated with Frontline Imatinib but Not for Patients Treated with Frontline Second-Generation Tyrosine Kinase Inhibitors

Background We previously performed an integrative genomic analysis for 47 chronic phase (CP)-CML patients at diagnosis who were specifically selected based on optimal or very poor outcome to tyrosine kinase inhibitors (TKIs). Patients who subsequently progressed to blast phase (BP) had a significantly higher frequency of cancer-related gene mutations at diagnosis compared with patients who achieved an optimal response (54% versus 16%). A novel mutational subtype associated with the formation of the Philadelphia (Ph) chromosome, termed Ph-associated rearrangements, were also described and included novel fusions, deletions and inversions adjacent to the BCR::ABL1 junction. These occurred at a higher frequency of patients who progressed to BP compared to those with an optimal response (33% versus 11%). Consequently, we sought to investigate the true incidence and effect of cancer-gene mutations and Ph-associated rearrangements (collectively termed additional mutational events, AMEs) detected at diagnosis and whether outcomes differ based on the TKI initiated. Aim To assess the impact on outcome and molecular response of AMEs detected at diagnosis for patients consecutively treated with imatinib compared to patients treated with second-generation TKIs (2G-TKI). Methods A recently validated hybridization capture sequencing method targeting genes involved in both myeloid and lymphoid malignancies was applied to available diagnostic RNA of consecutive clinical trial patients treated with either frontline imatinib or 2G-TKIs. The 200 imatinib-treated patients (TIDEL II; CML9) were commenced on 600mg daily of imatinib and managed with a highly proactive treatment intervention strategy for suboptimal response, which was either imatinib dose increase or switch to nilotinib. The 2G-TKI patients were enrolled in either DIRECT;CML12 (n=72), where patients commenced dasatinib 100mg daily before dose modification, or either ENESTxtnd or PINNACLE;CML11 (n=44) where patients commenced nilotinib 300mg twice daily. Variants in cancer genes with variant allele frequencies ≥5%, including single nucleotide variants, RNA splice altering variants, small insertions/deletions, gene fusions and focal gene deletions were assessed for pathogenicity using strict criteria. Ph-associated rearrangements were identified. Clinically relevant variants were confirmed as somatic and validated. Kaplan-Meier and cumulative incidence analyses were performed to assess the effect of AMEs on failure-free survival and key molecular outcomes by 36 months. Failure events were as defined by the European LeukemiaNet 2020. Results The incidence of AMEs for imatinib-treated patients was 31% (61/200): 33 (16%) cancer gene mutations and 36 (18%) Ph-associated rearrangements; 8 patients had both subtypes. In the 2G-TKI group, 41 AMEs were identified in 29% (34/116) of patients: 20 (17%) cancer gene mutations and 16 (14%) Ph-associated rearrangements; 2 patients had both subtypes. In total, 14 cancer genes were mutated. Consistent with other studies, ASXL1 mutations were most frequently detected: 18/200 imatinib patients (9%) and 9/116 2G-TKI patients (8%). Using 36-month outcomes as comparison, imatinib-treated patients with AMEs had inferior failure-free survival (84% versus 69%, P=.03), major molecular response (84% versus 72%, P=.02) and MR4 (62% versus 37%, P=.001). In contrast, outcomes in the 2G-TKI cohort were similar irrespective of the presence of AMEs, with regards to failure-free survival (94% versus 91%, P=.47) and achievement of major molecular response (88% versus 83%, P=.71). Interestingly, achievement of MR4 was delayed for patients with AMEs compared to those without AMEs at diagnosis: 51% versus 69%, P=.02 by 24 months; and 63% versus 70%, P=.40 by 36 months. No differences were observed for overall survival or transformation-free survival in either the frontline imatinib or 2G-TKI cohorts. Conclusion These results indicate that while the presence of AMEs do predict for inferior outcomes and molecular responses when patients are treated with frontline imatinib, the more potent 2G-TKIs may overcome the negative impact of the AMEs. The effect for imatinib treated patients was evident despite a starting dose of 600mg and more stringent treatment intervention than currently recommended. This supports a strategy of mutation analysis at diagnosis of CP-CML for optimal TKI selection. 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

Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients.

Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs.

Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy.

We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. For the 26 patients enrolled in this study, at 3, 6, 12, and 24months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3months than in patients without an MMR (809 and 420ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3months for predicting MMR achievement was 619ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0months, respectively; P = 0.020) and higher rates of DMR by 2years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619ng/mL. For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.

Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial

BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. Bristol-Myers Squibb.

Frequency and Outcome of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with BCR-ABL1 Clonal Hematopoiesis after Blast Clearance: Results from the Graaph-2014 Trial

BackgroundIG/TR-based minimal residual disease (MRD) is a faithful marker of response to therapy and the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). In adults with Philadelphia chromosome-positive (Ph+) ALL, MRD is commonly monitored by BCR-ABL1 transcript quantification, although its prognostic significance has not been compared to IG/TR MRD to date. Recently, it has been shown that BCR-ABL1 rearrangement may be found and persist in non-lymphoblastic cells in some patients. In the prospective GRAAPH-2014 trial, using a dual IG/TR and BCR-ABL1 MRD monitoring, we aimed to study the biological and clinical significance of persistent BCR-ABL1 clonal hematopoiesis (CH) in adults with de novo Ph+ ALL.Patients and MethodsThe study comprised 156 adults with de novo Ph+ ALL randomized in the GRAAPH-2014 trial. Bone marrow (BM) and peripheral blood (PB) follow-up (FU) samples were collected after each treatment cycle and before hematopoietic stem cell transplantation (HSCT). MRD monitoring was performed by quantification of both BCR-ABL1 transcripts and IG/TCR clonal rearrangements on all available samples and MRD quantification of genomic BCR-ABL1 breakpoint fusion was also performed for 37 patients. MRD results were considered discordant if more than one log10 difference or positivity/negativity discordance on the same FU sample was evidenced. Cell fractions from 14 peripheral blood mononuclear cells (PBMC) samples (T-cells, B-cells and monocytes) were FACS-sorted and evaluated for BCR-ABL1 expression. Achievement of major molecular response (MMR) defined as <0.1% BCR-ABL1/ABL1 ratio after the 4 treatment cycles (MRD4) was the primary endpoint of the clinical trial.ResultsQuantification of BCR-ABL1 transcripts and IG/TR MRD levels on 876 samples from 156 patients (456 BM and 542 PB) identified 54 out of 142 (38%) evaluable patients with consistently discordant MRD results in at least 3 different timepoints, suggesting the persistence of non-lymphoblastic BCR-ABL1-positive cells in these patients and BCR-ABL1 CH. Possible bias related to variable BCR-ABL1 expression was ruled out by genomic BCR-ABL1 quantification on 263 FU samples (r s=0.89, p<0.0001). Analysis of sorted PBMC fractions from discordant FU samples revealed the expression of BCR-ABL1 in mature B-cells, T-cells and/or monocytes in 11 patients, demonstrating the presence of BCR-ABL1 CH. Baseline characteristics of patients with BCR-ABL1 CH (CH+) showed no difference in terms of age, gender and white blood cell counts, but an enrichment in M-bcr breakpoints as compared to CH- patients (46.3% vs 17.1%, p<0.0001). As expected, the rate of MMR at MRD4 was lower (68% vs 95%, p<0.0001), with a trend for more patients who received alloSCT (38/54 (70%) vs 48/88 (55%), p=0.08).We then evaluated the clinical significance of BCR-ABL1 CH. Unexpectedly, CH+ patients had a significant lower cumulative incidence of relapse (CIR) (panel A, hazard ratio (HR) 0.37, 95% CI [0.15-0.90], p=0.03). However, this lower CIR did not translate into longer disease-free survival (DFS) (panel B, HR=0.85, 95% CI [0.44-1.63], p=0.63). Since an imbalance in alloSCT was observed between CH+ and CH- patients, we tested if the observed difference in CIR may be related to different alloSCT outcomes. When censoring patients at alloSCT, the difference in CIR was indeed no longer significant (subhazard ratio (SHR) 0.48, 95% CI [0.16-1.43], p=0.19). More interestingly, the benefit of alloSCT was restricted to CH- patients. Using alloSCT as a time-dependent variable, DFS was indeed improved by alloSCT in CH- (SHR 0.40, 95% CI [0.17-0.91], p=0.03, panel C) but not in CH+ patients (SHR 1.12, 95%CI [0.32-3.87], p=0.86, panel D) despite a non-significant interaction between CH status and alloSCT.ConclusionMore than one third of adults with de novo Ph+ ALL displays persistent measurable BCR-ABL1 signal during therapy, likely related to BCR-ABL1 CH. Strikingly, this condition is not associated with a higher risk of relapse nor with poorer overall outcomes in the GRAAPH-2014 trial. Moreover, our results suggest that patients with BCR-ABL1 CH may not be good candidates for alloSCT. By contrast, IG/TR MRD may allow to identify patients with the higher risk of relapse. These results highlight the need for implementation of IG/TR MRD in adult Ph+ ALL to guide therapeutic decisions. [Display omitted] DisclosuresRousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Straetmans: Alexion: Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: SANOFI: Honoraria; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding.

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.

A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP).Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated.Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1-17). Median observational period for survivors was 82 months (range, 48-118). Median WBC, Hb and platelet counts were 275x10 9/L (range, 8-765), 9.6g/dL (range, 5.8-14.6) and 560x10 9/L (range, 110-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades).Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents. DisclosuresNo relevant conflicts of interest to declare.

High STAT5A Expression is Associated with Major Molecular Response Achievement Failure of Chronic Phase Chronic Myeloid Leukemia Patients Receiving Hydroxyurea before Imatinib: A Cross-sectional Study

BACKGROUND: STAT5 is a transcriptional factor which when highly expressed in chronic myeloid leukemia (CML) cells stimulate proliferation and mediate resistance from tyrosine kinase inhibitors, resulting in major molecular response (MMR) failure. STAT5 has two isoforms, STAT5A and STAT5B. However, prolonged use of imatinib appears to only upregulate STAT5A pathway. In addition, the resistance conferred by STAT5A does not extend to other drugs such as hydroxyurea. Hence, STAT5A and STAT5B might have different functions in CML cells. AIM: The objective of the study was to determine the association of STAT5A and STAT5B expression with MMR failure in CML patients. METHODS: This was a cross-sectional study of CML patients in chronic phase with age ≥ 18 years old, receiving IM therapy ≥ 12 months, and previously given hydroxyurea. MMR status was evaluated and patients were categorized as achieved or failed to achieve MMR. Expression levels of STAT5A and STAT5B were conducted using RT-PCR methods. Associations between STAT5A expression, STAT5B expression, hydroxyurea duration, and imatinib duration with MMR achievement were calculated using logistic regression. RESULTS: A total of 118 patients were analyzed; 71.1% failed to achieve MMR. Multivariate logistic regression analysis showed statistically significant association between high STAT5A expression (odds ratio [OR]: 3.852; 95% confidence interval [CI]: 1.420–10.452; p = 0.008), STAT5A/STAT5B interaction (OR: 0.150; 95% CI: 0.038–0.593; p = 0.007), longer hydroxyurea administration (OR: 3.882; 95% CI: 1.023–14.733; p = 0.046), and shorter imatinib administration (OR: 0.333; 95% CI: 0.132–0.840; p = 0.020) with MMR achievement failure. After adjusting STAT5A expression with STAT5A/STAT5B interaction, high STAT5A expression independently increased the likelihood of MMR achievement failure only in high expression STAT5B patients (OR: 3.852; 95% CI: 1.420–10.452; p = 0.008). CONCLUSION: High STAT5A expression which is induced by high STAT5B is associated with MMR achievement failure of chronic phase CML patients who received hydroxyurea before imatinib. Longer duration of hydroxyurea and shorter duration of IM confound of STAT5A expression to MMR achievement failure.

TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia.

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow-up of 27·3months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow-up. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.

ALL-216: Outcomes of Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Molecular Response at Three Months of Therapy

Context The combination of tyrosine kinase inhibitors (TKI) with intensive chemotherapy improves outcome of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-pos ALL), particularly among patients in molecular response within three months of therapy. Objective The aim of this study is to identify prognostic factors for relapse and/or death in patients with Ph-pos ALL after 3 months of therapy. Design Retrospective analysis of patients who enrolled on prospective clinical trials of the combination of hyper-CVAD (HCVAD) with a TKI. Setting MD Anderson Cancer Center. Patients or other participants We analyzed 204 patients with newly diagnosed Ph-pos ALL who were treated with HCVAD with a TKI; imatinib (N=44), dasatinib (N=88), and ponatinib (N=72). Interventions Molecular response was assessed at CR, at 3 months, every 3 months during the first 2 years, and every 3-6 months thereafter. Allogeneic stem cell transplantation was offered at the discretion of patient and treating physician. Ponatinib dose was reduced to 15 mg daily, once CMR is achieved. Main outcome measures Progression -free survival (PFS) was calculated from the date of treatment initiation until date of relapse, or death. Overall survival (OS) was calculated from the time of treatment initiation until death. Results By multivariate analysis for PFS and OS in patients who achieved CMR within 3 months of therapy, ponatinib therapy was the only significant independent factor predicting for progression (P=0.028; hazard ratio [HR], 0.388; 95% confidence interval [CI], 0.166-0.904) and death (P=0.042; HR, 0.379; 95% CI, 0.149-0.966); among patients who did not achieve CMR within 3 months, the achievement of major molecular response was a favorable prognostic factor. Though the number of patients with MMR and without molecular response (i.e., no CMR/MMR) is limited, there was a tendency of improved PFS in patients who received allogeneic stem cell transplant. Conclusions The achievement of CMR within 3 months of therapy is the landmark for long-term survival. Ponatinib maintains CMR, and prevents relapse and death in patients with newly diagnosed Ph-pos ALL. MMR within 3 months was associated with improved survival compared to the lack of MMR within 3 months of TKI therapy.