Adult Chronic Myeloid Leukemia Patients Research Articles

The molecular signature of BCR::ABLP210 and BCR::ABLT315I in a Drosophila melanogaster chronic myeloid leukemia model

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from a balanced translocation leading to BCR::ABL1 oncogene with increased tyrosine kinase activity. Despite the advancements in the development of tyrosine kinase inhibitors (TKIs), the T315I gatekeeper point mutation in the BCR::ABL1 gene remains a challenge. We have previously reported in a Drosophila CML model an increased hemocyte count and disruption in sessile hemocyte patterns upon expression of BCR::ABL1p210 and BCR::ABL1T315I in the hemolymph. In this study, we performed RNA sequencing to determine if there is a distinct gene expression that distinguishes BCR::ABL1p210 and BCR::ABL1T315I. We identified six genes that were consistently upregulated in the fly CML model and validated in adult and pediatric CML patients and in a mouse cell line expressing BCR::ABL1T315I. This study provides a comprehensive analysis of gene signatures in BCR::ABL1p210 and BCR::ABL1T315I, laying the groundwork for targeted investigations into the role of these genes in CML pathogenesis.

Predictive performance of population pharmacokinetic models of imatinib in chronic myeloid leukemia patients.

Chronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram. A systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions. Eight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models. Menon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.

Correlation between BCR::ABL1 Transcript LEVEL in Circulating Extracellular Vesicles and BOTH the Molecular Response and the Ongoing Therapy: A Study on Adult CML Patients

Small extracellular vesicles (sEVs) have been shown to play a function in tumor growth and have been studied in Chronic Myeloid Leukemia (CML). Analysis of sEVs and their contents offers a non-invasive strategy that might identify messages transmitted by persisting leukemic cells. The sEVs recovered from CML patients may contain the BCR::ABL1 transcript, but its relationship to clinical and biological factors is still unclear. This study aims to connect the disease status and several clinical features with the BCR::ABL1 transcript levels in sEVs (BCR::ABL1-EV). sEVs were isolated by a commercial kit from 104 plasma samples of adult CML patients in molecular response: 18/104 (17%) in MMR and 86/104 (83%) in DMR assessed by RT-qPCR following the international scale. At sampling, 21/104 (20%) patients were treated with imatinib, 14/104 (13.5%) with nilotinib, 6/104 (5.5%) with dasatinib, 1/104 with bosutinib (1%), 27/104 (26%) with intermittent TKI therapy, and 24/104 (23%) were in treatment free remission (TFR). Taking advantage of digital PCR's (dPCR) sensitivity, it was used to detect the presence of BCR::ABL1 transcript in sEVs. The undetectable samples by RT-qPCR on cells were 38/104 (36.5%), while by dPCR on sEVs were 13/104 (12.5%). This difference resulted statistically significant (p<0.0001) (Fig 1A). In terms of sensitivity, dPCR was able to detect more BCR::ABL1 transcript in the sEVs than in the cells (p= 0.0052), suggesting the release of sEVS shuttling BCR::ABL1 transcript by CML cells resident in the bone marrow (Fig 1B). Considering the quantity of BCR::ABL1 transcript molecules, the BCR::ABL1-EV showed a decrease at the deepening of the MR classes and there was a significant difference between MR3.0 and MR4.5 and MR5.0 (p= 0.0226 and p=0.0101, respectively) (Fig 1C). By gathering overall samples according to MMR and DMR definition, the BCR::ABL1-EV resulted statistically different (p= 0.0017), presenting an increased significance when compared with the analysis on the different MR classes (Fig 1D). A significant difference between BCR::ABL1-EV and the ongoing therapy was observed. For this analysis, nilotinib, dasatinib, and bosutinib were considered together as “2 nd generation TKI”. The BCR::ABL1-EV were significantly higher in samples from patients in intermittent therapy compared to those from patients treated with imatinib (p=0.0398). No statistical difference resulted by other comparisons, even if a trend can be appreciated (Fig 1E). This evidence may be due to the therapy duration, since the mean therapy duration is 111 months and 45 months for imatinib and 2 nd generation TKI, respectively. Despite that, no linear regression between therapy duration and BCR::ABL1-EV. Another fascinating hypothesis is that the difference could be related with mechanisms activated by the different drugs. Further analysis will clarify this point. Interestingly, when comparing the results obtained by dPCR on cells and sEVs, a significant difference was observed in samples of patients under intermittent treatment. A trend can be appreciated in the other conditions, with except for imatinib (Fig 1F). In conclusion, dPCR associated with sEVs analysis confirmed its higher sensitivity to detect even low levels of target and it is able to identify the presence of not-circulating leukemic cells releasing BCR::ABL1 positive sEVs. Moreover, the analysis of the BCR::ABL1 transcript on sEVs revealed a transcript reduction at the deepening of the MR classes, discriminated between MMR and DMR, and correlates with the ongoing therapeutic strategy. Further analysis will clarify the mechanisms at the bases of this correlation. This is the first report about the application of this approach on a cohort of adult CML patients, but strongly suggests how a liquid biopsy approach is able to identify active leukemic cells not otherwise detectable. It opens to the identification of different sub-sets of patients presenting different vesicular BCR::ABL1 transcript levels. The different sub-sets could be related to the therapy response as well as the eligibility to TKI suspension, two of the main hot points in the present CML patients' management.

Interleukin 10 (IL10) and IL15 Significantly Decreased in Chronic Myeloid Leukemia Patients Presenting with Tyrosine Kinase Inhibitor (TKI) Withdrawal Syndrome (TWS). Results from the Prospective, Explorative and Multicenter « Kiwis » Study Designed for TWS. Clinicaltrial.Gov ID: NCT03996096; Study Number: 18-206

Aims Treatment-free remission (TFR) has been included in practice guidelines as a new management goal for chronic myeloid leukemia (CML) patients, implying discontinuation of tyrosine kinase inhibitors (TKI). Paradoxically, TKI discontinuation gives rise to musculoskeletal pain and/or flushing, known as TKI withdrawal syndrome (TWS), in approximately 25% of patients with a reported median time of occurrence of 6 weeks. This syndrome is assumed to be caused by cytokine release, mast cell regrowth, or reactivation of an underlying inflammatory state. The KIWIS trial aimed at assessing these hypotheses by prospectively dosing biological markers before and after TKI discontinuation looking for any significant variation to be correlated to TWS. The secondary objectives were: description of the manifestations of TWS, assessment of TFR. Here, we will only focus on the primary objective. Methods The KIWIS study ( Clinicaltrial.govID: NCT03996096) was a multicenter prospective cohort of adult CML patients who had been treated with TKIs for at least 5 years, with a minimum of 2 years in deep molecular response (MR4.5). Patients with a history of inflammatory disease, those taking steroids, or those unable to complete the short form of the Brief Pain Inventory (BPI) were not included. BPI was used to assess pain severity and its impact on daily functioning. The arithmetic mean of the four severity items was used to score the severity of pain at different time points and identify patients with TWS. Blood samples were collected at baseline (M0), 1 month (M1), 2 months (M2), and 3 months (M3) post-discontinuation of TKI. We explored the following biomarkers: CRP, Rheumatoid Factor, tryptase, calcium, phosphate, Creatin Kinase, IL2, IL6, IL10, TGFβ, TNFα, IFNϒ, VEGF, PDGFβ, IL15, Crosslaps (CTX), Collagen pro-peptide type 1 (PINP1), and parathormone. Each patient served as their own control, and any variation of a biomarker by 20% from baseline was considered clinically significant. The BPI form was completed at the same time points as BCR-ABL follow-up: M0, M1, M2, M3, M4, M5, M6, M8, M10, and M12 following TKI withdrawal. The study was powered to include 50 patients. Results Out of the 50 patients, 16 (32%) developed TWS within the first 3 months, with a median onset time of 2 months. Patients' characteristics are displayed in table1. The baseline characteristics of patients in the TWS and non-TWS groups were similar. The duration of CML treatment was significantly longer in TWS patients compared to non-TWS patients (median: 9, Interquartile Range (IQR) [7-13] vs 7, IQR [6-8], p=0.039, respectively). No predictive factor for developing TWS were observed considering patients' characteristics and BPI scores at M0 in the univariate analysis. At M0, there were no significant differences between the two groups in terms of the concentration of each specific biomarker. In the TWS group, IL10, IL15, and IFNϒ levels decreased between inclusion and the M3 time point. For IL10, the median was 0.18 pg/ml (IQR: 0.12; 0.31) vs. 0.12 (IQR: 0.08-0.17), p=0.002; for IL15, 2.30 pg/ml (IQR: 1.77; 2.92) vs. 1.81 (IQR: 1.48; 2.25), p=0.026; and for IFNϒ, 5.92 pg/ml (IQR: 4.17; 12.49) vs. 4.24 pg/ml (IQR: 2.64; 7.99), p=0.036. In the non-TWS group, no significant differences were found. Changes in IL10 were positively correlated with changes in IL15 from M0 to M3 in all patients: r=0.42, p=0.009. No significant variations were observed in the two patient groups regarding the other biomarkers. Figure 1 exemplifies the evolution of IL10 (A: in TWS patients; B: in non-TWS patients) at M0 and M3. One patient missed the M3 time point sample. Conclusion This is the first study designed to prospectively investigate biomarkers associated with TWS. Our results suggest that TWS is not a cytokine-release-like syndrome but a distinct entity significantly associated with a decrease in IL10, IL15, and IFNϒ concentrations. It is worth noting that IL10 is an anti-inflammatory cytokine known to reduce pain; the role of IL15 and IFNϒ remains to be clarified. We hope that this study will pave the way for further investigations to fully understand the pathophysiology of TWS.

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

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

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia

Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.

The mRNA Expression of PTEN, LEF1, JAK3, LC3 and p62/SQSTM1 Genes in Patients with Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a progressive myeloproliferative disorder resulting from forming a chimeric BCR-ABL gene. The proteins derived from this gene can affect some genes from various signaling pathways such as PI3K/AKT/Wnt/catenin/JAK/Stat involved in proliferation, differentiation, cell death, and genes related to autophagy. Imatinib is the first-line treatment for CML patients, with durable and proper responses in Iranian children and adult CML patients. Hence, we aimed to evaluate the mRNA expression of some selected key genes from those pathways in patients with CML before and under treatment. In the case-control study, the mRNA expression of PTEN, LEF1, JAK3, LC3 and p62 genes were measured in 51 CML patients (6 patients before treatment and 45 patients under treatment with imatinib mesylate) and 40 healthy controls using the Real-time PCR method. The mRNA expression of PTEN and P62 were significantly higher in newly diagnosed patients than in controls (P<0.0001 and P = 0.0183, respectively), while the expression of the LC3 gene was significantly lower in the untreated newly diagnosed group than in control subjects (P = 0.0191). The expression level of PTEN, LEF1, JAK3 and P62 genes were significantly decreased in patients under treatment than in the group before treatment (P = 0.0172, P = 0.0002, P = 0.0047 and P = 0.0038, respectively). A positive correlation was seen between the gene expression of P62 and BCR-ABL in the patients under treatment (r 0529, P = 0.016). Our findings showed that the changes in expression of these genes were related to the patient's treatment. Due to the key role of these genes in proliferation, differentiation and tumor suppression, it is proposed that these genes may be helpful for follow-up of treatment in CML patients.

A Phase II, Single-Arm Study of De-Escalation and Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with Nilotinib in First-Line Therapy Followed By a Second Attempt after Nilotinib and Asciminib Combination: Dante Study

Introduction: Treatment-free remission (TFR) is considered one of the main goals of therapy in patients with chronic myeloid leukemia (CML). Several studies have shown that treatment discontinuation can be successfully achieved in roughly 50% of patients with a sustained deep molecular response (sDMR). However, the remaining 50% require reintroduction of tyrosine kinase inhibitor (TKI) therapy. Although about 90% of patients who experience molecular relapse regain a major molecular response (MMR) after restarting TKI therapy, due to poorly understood mechanism(s), the probability for those patients of failing a second attempt to discontinue TKI (TFR2) is higher compared to the first attempt. The above-mentioned data implies that, to aim to a second TFR, a different therapeutic strategy might be needed. Asciminib (ASC), unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is an allosteric, first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action that has shown efficacy in heavily pre-treated patients after two or more TKIs (Rea et al. 2021). An ongoing phase I dose-finding study (NCT02081378) has shown that ASC combined with TKI is both effective and well tolerated in heavily pretreated CML patients, suggesting that combination treatment between an allosteric and an ATP-competitive TKI may deepen clinical responses without serious safety concerns (Mauro et al. 2019). The changes introduced in the DANTE study (NCT03874858) by the amendment 4 aim to assess whether ASC in combination with nilotinib (NIL) can lead to higher and more durable TFR2 rates than those reported in other studies. Methods: After providing written informed consent, the TFR2 phase will enroll - from 29 Italian centers, approximately 60-70 adult CML patients in chronic phase, who have been (i) treated for at least 3 calendar years with NIL, (ii) failed a first TFR attempt, (iii) restarted NIL for at least 1 year and (iv) fulfill all inclusion/exclusion criteria. The study consists of 4 phases: screening, re-induction (week 0-96), TFR2 (week 96-144) and follow up phase. In the re-induction phase, patients will be treated with ASC 40 mg BID and NIL 300 mg BID for 96 weeks and will have scheduled biweekly/monthly visits until week 12, and then every 12 weeks. NIL dose may be less than 300 mg BID if appropriate by clinical judgement but must be at least 300 mg daily. During re-induction, sDMR is defined as no loss of MR4.0 (BCR-ABL level ≤ 0.01% IS) in any BCR-ABL RQ-PCR assessment. Patients with sDMR at the end of re-induction will enter in TFR2 and ASC plus NIL will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed during re-induction or results are not available, the patient will not be eligible for TFR2 and will be treated with NIL 300 mg BID until the end of the TFR2 stage (week 144). Patients not eligible for TFR2 but with a response more than an MMR will continue treatment with ASC and NIL until the end of re-induction (week 96) and then continue NIL monotherapy at 300 mg BID until the end of the TFR2 stage (week 144). Patients with loss of MMR at any time during re-induction or during NIL monotherapy will be discontinued from the study. If MMR loss occurs during TFR2, NIL 300 mg BID will be restarted and administered until end of study (Fig1). Endpoints: The primary endpoint is the percentage of patients in TFR 48 weeks after stopping NIL and ASC combination. Key secondary endpoints are: (i) percentage of patients eligible for TFR2, (ii) the number of patients with loss of MMR in TFR2 and regain MMR/DMR by the end of the TFR2 stage (iii) BCR-ABL kinetics in the different study phases (iv), OS, TFS and PFS and (v) the safety of the combination. The TFR2 stage is descriptive and no formal statistical testing is necessary or applicable. Conclusions: The expected results from this phase II interventional study, will potentially represent a milestone in treatment strategy for those patients who aim to discontinue NIL for the second time by providing them with several benefits including an improved quality of life.

Follow-up of Chronic Myeloid Leukemia Patients whose Tyrosine Kinase Treatment Was Stopped: Case Series

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR ABL1 fusion protein with translocation t(9;22) (Philadelphia chromosome-Ph). With recent studies, it has been understood that the treatment of adult chronic phase CML patients who have achieved a deep molecular response with the use of TKI and can maintain this response for a long time can be safely terminated; It has been observed that it is possible for patients to remain in long-term molecular remission without the use of TKI. Based on these studies, we will try to present the follow-up processes of chronic phase CML patients, who were followed up in our clinic and whose TKI treatment was stopped. First case; A 69-year-old female patient was diagnosed with Ph positive chronic phase CML in 2008. The imatinib treatment of the patient, who had been using imatinib for about 13 years and was bcr-abl negative for the last 3 years, was discontinued in December 2021. In the 2nd and 4th months, the requested bcr-abl was negative. Second case; a 42-year-old male patient was diagnosed with Ph-positive chronic phase CML in 2006. The patient, who had been using imatinib for about 16 years and was bcr-abl negative for the last 3 years, was discontinued in April 2022. bcr-abl came back negative. Third case; a 42-year-old female patient was diagnosed with Ph positive (IS: 31,824) chronic phase CML in 2019. He received Nilotinib and Dasatinib treatment after he had an allergic skin reaction using imatinib for about 2 years. The patient had drug intolerance and was bcr-abl negative for about 2 years, and the treatment was stopped. The 1-month follow-up was negative for bcr-abl. Fourth case; Imatinib was started in a 50-year-old female patient with the diagnosis of Ph-positive chronic phase CML in 2012. Due to imatinib intolerance, the treatment of the patient who was using nilotinib and was bcr-abl negative for the last 3 years was discontinued in February 2021. The bcr-abl negativity continues in the follow-ups. Fifth case: A 58-year-old female patient was diagnosed with Ph-positive chronic phase CML in 2013. The imatinib treatment of the patient, who has been using imatinib for about 8 years and has been negative for bcr-abl for the last 3 years, was discontinued in November 2021. The bcr-abl negativity continues in the follow-ups. STIM 1(Stop Imatinib) study is the first multicenter, non-randomised, prospective study on TKI termination.Then, TWISTER, A-STIM, ENEST, STOP2GTKI, EURO SKI studies were carried out.In these studies, TKI treatment was discontinued in patients who used TKI for at least 3 years and had a major molecular response for the last 2 years. Remission was achieved in approximately 50% of the patients who were followed up without medication. In our study; The treatment of patients who had been using TKI for 5 years and had a major molecular response for about 2 years was stopped. The follow-up of the patients (minimum: 1 month, maximum: 15 months) continues, and all of them are in remission.

Chronic Myeloid Leukemia: Part II—Cost of Care Among Patients in Advanced Phases or Later Lines of Therapy in Chronic Phase in the United States from a Commercial Perspective

Background: Tyrosine kinase inhibitors (TKIs) are the standard-of-care treatment for chronic myeloid leukemia in chronic phase (CML-CP). Despite advances in therapy, there remains a proportion of patients with CML-CP that are refractory/intolerant to TKIs, and these patients cycle through multiple lines of therapy. Moreover, even with TKIs, some patients progress to accelerated phase/blast crisis (AP/BC), which is associated with particularly poor clinical outcomes. Objectives: To describe real-world treatment patterns, healthcare resource utilization (HRU), and costs of patients with CML-CP reaching later lines of therapy or progressing to AP/BC in the United States. Methods: Adult CML patients from administrative claims data (January 1, 2000–June 30, 2019) were classified by health state: on third-line (CML-CP On Treatment), on fourth or later lines (CML-CP Post-Discontinuation), or progressed to AP/BC (CML-AP/BC). Outcomes were assessed by health state. Results: There were 296 (4620 patient-months), 83 (1644 patient-months), and 949 (25 593 patient-months) patients classified in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohorts, respectively. Second-generation TKIs (nilotinib, dasatinib, and bosutinib) were most commonly used in the CML-CP On Treatment (69.1% of patient-months) and CML-CP Post-Discontinuation cohorts (59.1% of patient-months). Three-month outpatient incidence rates (IRs) were 7.6, 8.3, and 7.0 visits in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $597 per service. Three-month inpatient IRs were 0.6, 0.7, and 1.4 days in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $5892 per day. Mean hematopoietic stem cell transplantation cost was $352 333; mean 3-month terminal care cost was $107 013. Discussion: Cost of CML care is substantial among patients with CML reaching third-line, fourth or later lines, or progressing to AP/BC, suggesting that the disease is associated with a significant economic and clinical burden. From third-line to fourth or later lines, HRU was observed to increase, and the incidence of inpatient days was particularly high for those who progressed to AP/BC. Conclusion: In this study, patients with CML cycling through TKIs in later lines of therapy or progressing to AP/BC experienced substantial HRU and costs, suggesting unmet treatment needs.

Chronic Myeloid Leukemia: Part II-Cost of Care Among Patients in Advanced Phases or Later Lines of Therapy in Chronic Phase in the United States from a Commercial Perspective.

Background: Tyrosine kinase inhibitors (TKIs) are the standard-of-care treatment for chronic myeloid leukemia in chronic phase (CML-CP). Despite advances in therapy, there remains a proportion of patients with CML-CP that are refractory/intolerant to TKIs, and these patients cycle through multiple lines of therapy. Moreover, even with TKIs, some patients progress to accelerated phase/blast crisis (AP/BC), which is associated with particularly poor clinical outcomes.Objectives: To describe real-world treatment patterns, healthcare resource utilization (HRU), and costs of patients with CML-CP reaching later lines of therapy or progressing to AP/BC in the United States.Methods: Adult CML patients from administrative claims data (January 1, 2000–June 30, 2019) were classified by health state: on third-line (CML-CP On Treatment), on fourth or later lines (CML-CP Post-Discontinuation), or progressed to AP/BC (CML-AP/BC). Outcomes were assessed by health state.Results: There were 296 (4620 patient-months), 83 (1644 patient-months), and 949 (25 593 patient-months) patients classified in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohorts, respectively. Second-generation TKIs (nilotinib, dasatinib, and bosutinib) were most commonly used in the CML-CP On Treatment (69.1% of patient-months) and CML-CP Post-Discontinuation cohorts (59.1% of patient-months). Three-month outpatient incidence rates (IRs) were 7.6, 8.3, and 7.0 visits in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $597 per service. Three-month inpatient IRs were 0.6, 0.7, and 1.4 days in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $5892 per day. Mean hematopoietic stem cell transplantation cost was $352 333; mean 3-month terminal care cost was $107 013.Discussion: Cost of CML care is substantial among patients with CML reaching third-line, fourth or later lines, or progressing to AP/BC, suggesting that the disease is associated with a significant economic and clinical burden. From third-line to fourth or later lines, HRU was observed to increase, and the incidence of inpatient days was particularly high for those who progressed to AP/BC.Conclusion: In this study, patients with CML cycling through TKIs in later lines of therapy or progressing to AP/BC experienced substantial HRU and costs, suggesting unmet treatment needs.

Skin and soft tissue infections in adolescent chronic myeloid leukemia under dasatinib treatment.

Although skin complications are common adverse events from tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML), no reports have focused on skin and soft tissue infections (SSTIs) associated with TKI use. We herein present five episodes of SSTIs in three CML patients under dasatinib treatment. All patients were adolescents and had been receiving dasatinib for more than 4years. In contrast, none of 41 adult CML patients experienced SSTIs in a retrospective analysis. Our findings suggest that long-term dasatinib treatment in adolescent patients may be associated with the increased risk of SSTIs.

Hsa-miR-181a-5p, hsa-miR-182-5p, and hsa-miR-26a-5p as potential biomarkers for BCR-ABL1 among adult chronic myeloid leukemia treated with tyrosine kinase inhibitors at the molecular response

BackgroundTyrosine kinase inhibitors (TKIs) as first-line therapy for Chronic Myeloid Leukemia (CML) show a high success rate. However, a low number of patients with long-term treatment-free remission (TFR) were observed. Molecular relapse after imatinib discontinuation occurred at 50% at 24 months, with 80% occurrence within the first 6 months. One of the reasons for relapse is untimely TKIs discontinuation caused by large errors from estimates at very low-level or undetectable disease, thus warranting new biomarkers for CML.MethodsNext Generation Sequencing (NGS) was used to identify microRNAs (miRNAs) at the molecular response in CML adult patients receiving TKIs treatment. A total of 86 samples were collected, 30 from CML patients responsive and 28 from non-responsive to imatinib therapy, and 28 from blood donors. NGS was conducted whereby 18 miRNAs were selected and validated by real-time RT-qPCR in triplicate.ResultsHsa-miR-181a-5p was expressed significantly (p-value< 0.05) with 2.14 and 2.33-fold down-regulation in both patient groups, respectively meanwhile hsa-miR-182-5p and hsa-miR-26a-5p were significant only in the non-responsive group with 2.08 and 2.39 fold up-regulation. The down-regulation was consistent with decreased amounts of BCR-ABL1 in patients taking TKIs regardless of molecular responses. The up-regulation was consistent with the substantial presence of BCR-ABL1 in CML patients treated with TKIs at the molecular response.ConclusionsTherefore, these miRNAs have potential as new therapeutic biomarkers for BCR-ABL1 status in adult CML patients treated with TKIs at molecular responses. These could improve current approaches and require further analysis to look for targets of these miRNAs in CML.

COVID-19 infection in chronic myeloid leukemia patients

Introduction: Corona virus disease 2019(COVID-19) is an infectious disease caused by newly discovered coronavirus SARS CoV-2 (Severe acute respiratory syndrome coronavirus 2). Majority of the COVID-19 infections have mild symptoms in general populations but symptoms may be more severe in immunocompromised and elderly patients and may be in CML populations also. We expected most of CML patients in elderly age group may develop severe symptoms of COVID-19 and its severity may vary in different phases of the CML and different types of TKI being used.&#x0D; Method: From January 2020 to June 2021 all adult CML patients receiving treatment from Patan Hospital, identified with SARS Cov-2 infection were included in the study. Those patients who had final outcome from COVID-19 infection was taken.&#x0D; Result: The prevalence of SARS CoV-2 infection in CML population in our hospital is 2.60%. The COVID-19 infection was seen more on female population and younger age group less then 60 years old. Even though the infection rate was higher in the younger age group and infection rate was lesser in CML-CP group, mortality was higher in elderly and advances age group which was statically significant. Regardless of their symptoms, stages, severity of the symptoms, different TKI being used about 92% have fully recovered from COVID-19 infection.&#x0D; Conclusion: About 92% of CML patients had fully recovered from COVID-19 infection. In our study advanced stage and elderly age group were associated with more severity of the disease and higher mortality rate.

The Outcomes of Ponatinib Therapy in Patients With Chronic Myeloid Leukemia Resistant or Intolerant to Previous Tyrosine Kinase Inhibitors, Treated in Poland Within the Donation Program

IntroductionTyrosine kinase inhibitors (TKIs) have greatly improved the treatment outcome for most patients with chronic myeloid leukemia (CML). Ponatinib is a new pan-inhibitor of TK active in resistant CML. This study aimed to evaluate the efficacy and safety of ponatinib in patients suffering from CML. Patients and methodsThis multicenter, non-randomized, observational, retrospective study evaluated the efficacy and safety of ponatinib administered in adult CML patients in any disease phase, including those with a detected ABL T315I mutation, which were resistant or intolerant to previous-generation TKIs. The study comprised 43 patients benefiting from the ponatinib donation program who were treated in 16 Polish centers. ResultsFor patients who started treatment with ponatinib in chronic phase (CP) (n = 23) and in accelerated phase (AP) (n = 3) the median time on ponatinib was 19.5 months (range: 1.0-35.4), and 31.7 months (range: 31.0-34.1), respectively. All these patients were in CP after 1 month of treatment and at the end of observation – none of them progressed to AP or blastic phase (BP) during the study, meaning that progression-free survival was 100% at the end of observation (35.4 months). The estimated 2-year survival in this group of patients was 84%. For all 43 patients, median survival was not reached (lower quartile 6.3 months), and estimated 2-year survival was 60%. ConclusionOur analysis confirmed ponatinib efficacy in a significant proportion of patients heavily pre-treated with TKIs achieving durable responses in both CP and AP/BP CML groups.

FINAL Analysis of a PAN European STOP Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI Study

▪Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). Around 40-60% of patients with stable DMR [deep molecular response, corresponding to <0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with recommendations from the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European Stop TKI) trial, 62% were in major molecular response (MMR: <0.1% BCR-ABL1 IS) at 6 months. DMR duration before TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up.Aims: The main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring.Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal than 40% and less or equal than 35%, respectively.Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74, DMR not confirmed n=11, atypical/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years). Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without MMR loss. At 6 months, 713 patients were available (without molecular test at 6 months: n=6, TKI restart without relapse: n=9). Since 434 patients (61%) [95% CI: 57-64] remained without relapse during the first 6 months, the null hypothesis was rejected (p<0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42-49], the null hypothesis of 35% or less was rejected (p<0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred.Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis.Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years. [Display omitted] DisclosuresHochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Novartis: Research Funding; BMS: Research Funding; Janpix: Research Funding; Pfizer: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Clinical Characteristics and Late-Line Treatment Patterns of Patients with Chronic Myeloid Leukemia Who Received 2 Prior Lines of Tyrosine Kinase Inhibitor Therapy in US Community Oncology Practices

BACKGROUND: Current treatment guidelines recommend tyrosine kinase inhibitors (TKIs) as first-line and second-line treatment options for patients with chronic myeloid leukemia (CML). 1,2 However, approximately 20% of CML patients fail to respond to the first- and second-generation TKIs, and evidence-based guidelines for late-line treatment options after failure/intolerance to TKIs are limited. 3,4 Therefore, this study sought to describe the clinical characteristics and real-world treatment patterns of CML patients who received 2 prior lines of TKI therapy.METHODS: A retrospective cohort design was utilized to identify adult CML patients who initiated a new line of therapy (LOT) after 2 prior lines of TKI therapy between 4/2013 and 12/2020 in the Florida Cancer Specialists network's electronic health records (EHR) database. The index LOT date was the start date of a new CML treatment regimen in LOT≥3 after 2 prior lines of TKI therapy. Patients were followed until 1 of the following occurred: death, loss to follow-up (last structured activity in EHR), or end of study period (3/31/2021). Demographic and clinical characteristics were captured during the baseline period starting 3 months prior to the initial CML diagnosis until the index LOT date and included age, gender, race, Eastern Cooperative Oncology Group performance status (ECOG PS) and comorbidity burden. Treatment patterns of all available LOTs from initial CML diagnosis were investigated and the following metrics were captured: regimen details of systemic CML therapies, duration of LOT, treatment-free interval. This study was descriptive in nature and no inferential statistics were computed.RESULTS: A total of 157 patients who initiated a new CML treatment regimen in LOT≥3 after 2 previous lines of TKI therapy were included in this study. The median age of the study sample at initial CML diagnosis was 63.8 years, 57.3% of the sample were male, and 50.3% were White. At index LOT, 46.5% of the sample had an ECOG PS score of 0-1, 5.1% had ECOG PS score of 2-4, and 48.4% had an unknown ECOG PS score. The majority of the sample initiated the index LOT in LOT 3 (n=151; 96.2%) vs in LOT 4 (n=6; 3.8%). The median duration of the index LOT was 6.6 months with median follow-up from index LOT being 23.0 months. After 2 prior lines of TKI therapy, 93.0% of the sample continued on TKIs only, 1.3% initiated a non-TKI CML drug, and 5.7% received a combination of CML drugs. Dasatinib (31.2%) and imatinib (30.6%) were the most commonly used TKIs in the index LOT. There was significant variability in the treatment sequences across LOTs, however, 50.3% of the sample restarted the same TKI in their index LOT which had been used in a prior LOT. A total of 65 patients (41.4%) initiated a new LOT after the index LOT, and the treatment-free interval following the index LOT was 1.8 months, on average.CONCLUSIONS: The majority of the CML patients who received 2 prior lines of TKI therapy continue to cycle through additional LOTs containing TKIs, and half of the patients restart the same TKI used in a prior LOT. The findings of this study highlight the need for better novel therapies that can fill the treatment gap for CML patients who are refractory or intolerant to TKIs. REFERENCES1. Deininger MW, Shah NP, Altman JK, et al. Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(10):1385-1415.2. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv41-iv51.3. Perrotti D, Jamieson C, Goldman J, et al. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254-2264.4. Cortes J, Lang F. Third-line therapy for chronic myeloid leukemia: current status and future directions. J Hematol Oncol. 2021;14(1):44. DisclosuresPatel: Novartis Pharmaceuticals Corporation: Research Funding. Raju: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Coutinho: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Lunacsek: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Deyoung: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Iorga: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Cao: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company.

CML-252: Current Patient Management and Outcomes of Chronic Myeloid Leukemia (CML) in Colombia: On Behalf of ACHO’s RENEHOC Investigators

Context: Tyrosine kinase inhibitors (TKIs) dramatically changed outcomes in CML; achieving and maintaining treatment milestones is highly dependent on adherence. Colombia subscribes a principle of universal health coverage; however, there is significant difference in access to high-cost drugs between different insurance types (Subsidized [SS] vs Contributory [SC]). Objective: To describe the current patient management and outcomes of CML in Colombia and possible factors associated with outcomes. Design: ACHO’s hematological disease registry (RENEHOC) is a multicenter study that has collected information on CML patients since 2019. Setting: RENEHOC is a real-world registry that captures information from 16 academic and general community centers in 5 cities in Colombia. Patients or Other Participants: Adult CML patients. Interventions: Due to its observational nature, all treatment decisions depend on treating investigator preferences. Main Outcomes Measures: RENEHOC is an online database. This report summarizes data on CML patients as of May 2020, focused on general descriptive statistics. The Kaplan-Meier method was used to assess progression free survival (PFS) rates, defined as progression to AP/BP or death. Hazard ratios (HR) using Cox proportional hazards regression modeling were estimated. Results: A total of 442 patients have been registered with a median follow-up of 60 months (IQR 26.5–106.5). At diagnosis, mean age was 54 years (SD 15.23), 58.6% (259) were males, most patients were in chronic phase (92.3%) and most had intermediate or high risk Sokal (35.6% and 36%, respectively). Median time from symptoms to diagnosis was 4 weeks (IQR 1–11), with no difference between SS and CS (p=0.54) and from diagnosis to treatment 4 in SS vs 0 in CS (p=0.041). Imatinib was the first-line treatment in 62.9%, dasatinib in 20%, and nilotinib 15%. Median OS and EFS were 60 (IQR 26.5–106.5) and 51 months (IQR 21–91), respectively. Only 7 (2.5%) patients died; all deaths were CML-related. Type of insurance (median EFS 51 CS vs 38.5 months SS; p=0.04), phase at diagnosis (p=0.039), and achieving MMR with first-line were the only factors related with EFS. Conclusions: OS for CML is excellent (97.5%) in Colombian patients. Unequal treatment between insurance types appears to have an impact on outcomes, which has to be addressed.

Quality of life among chronic myeloid leukemia patients in the second-line treatment with nilotinib and influential factors.

This study aims to evaluate the quality of life (QoL) of chronic myeloid leukemia (CML) patients prescribed with nilotinib as a second-line therapy and explores the influential factors. A multicenter retrospective survey was conducted via face-to-face interviews based on the EORTC QLQ-C30 questionnaire. A total of 121 adult CML patients resistant to imatinib and used nilotinib for at least 3months were enrolled. The influential features were assessed by multiple linear regression models. Patients had the mean age of 47.49 (SD = 13.67) years, dominated by middle-aged and male groups. The mean scores of functions ranged from 75 to 83, and those of symptoms were from 5 to 28, with the highest of fatigue (28.28), insomnia (22.87), and pain (21.07). The mean global health status/QoL score was 67.70 (SD = 16.80) with considerable financial difficulties (52.34 (SD = 32.15)). Male patients reported higher functional scores and fewer symptoms compared with female patients. All aspects of QoL became worse with increasing age. Besides age and gender, level of education, duration of nilotinib usage, and comorbidities were also significantly influential factors in many QoL domains. A predicted model for expected mean scores of QoL domains was built based on these factors. The CML patients treated with nilotinib had the above-moderate QoL scores, a light decrease of functional scores, great financial difficulties, and still experienced symptoms. Strategies and more therapeutic considerations to enhance QoL for CML patients targeted toward women, the old, low educational level, and long duration of nilotinib usage, and many comorbidities are needed in the setting.

Molecular Responses and Outcomes of Pediatric CML Treated with Front-Line Imatinib and a Comparison between Pediatric and Adult Cohorts

Background and PurposeChronic myeloid leukemia (CML) is a rare disease in children and constitutes 2% to 3% of pediatric leukemia. Imatinib, a potent tyrosine kinase inhibitor (TKI), is well established as a standard treatment for newly diagnosed adults with CML in chronic phase. Many pediatric oncologists have followed the treatment guidelines that originally designed for adult patients. There have been rare studies reporting the molecular responses to imatinib in children with CML. The aim of this multi-center study in Taiwan was to assess the treatment responses and outcomes of front-line imatinib therapy in pediatric CML. A comparison between pediatric and adult CML patients was also performed.Patients and MethodsBetween 2002 and 2017, there were 53 newly diagnosed children, age < 18 years old, with CML in chronic phase receiving front-line imatinib therapy with a daily dosage of 300 mg to 400 mg. b3a2, b2a2, b3a2+b2a2, and b3a3 BCR-ABL1 transcripts were detected in 32, 19, 1 and 1 patient(s) respectively. Fifty-two patients with b3a2 and or b2a2 were enrolled in this study. Peripheral blood BCR-ABL1 levels expressed as International Scale (IS) were measured by TaqMan RQ-PCR assay with the lab-specific conversion factor every 3 months in a central laboratory. The criteria of the European LeukemiaNet regarding optimal response were adopted: major cytogenetic response (MCyR, IS < 10%) at 3 months, complete cytogenetic response (CCyR, IS < 1%) at 6 months and major molecular response (MMR, IS < 0.1%) at 12 months (Blood 2013). Molecular response of a patient was censored if the patient received hematopoietic stem cell transplantation (HSCT), switched to 2nd-generation TKI, or died. An adult cohort of 685 patients who had molecular measurements in the same central laboratory, presented partly in ASH 2014 (Blood 2014. 124: 4544a), was updated for the comparison analysis.ResultsOf the 52 pediatric CML patients, 31 were males, the median age at diagnosis of 14.2 years (range, 1.4-17.9). The WBC count ranged from 24.5 to 806.5×109/L (median, 294.4). High Sokal risk group was only observed in 4% and 14.6% for score adopted for younger than 45 years old, respectively. Eight patients went on to receive HSCT, and 20 patients were shifted to 2nd-generation TKIs (14 dasatinib, 6 nilotinib), including 3 achieved optimal responses because of imatinib intolerance. Compared with the adult cohort, there was no statistical difference in the frequency of transcript subtypes. Pediatric patients classified as Sokal high-risk group were significantly lower than those in adult cohort (P < 0.0001).The molecular responses and outcomes of the pediatric cohort are summarized in Table 1. The median followed-up duration was 74.6 months (range, 3.0-182.1). Optimal responses at 3 months, 6 months and 12 months following imatinib therapy were achieved in 52.0%, 39.1% and 21.7%, respectively. MMR and MR4.5 (IS ≤ 0.0032%) were achieved in 48% and 15% of pediatric patients, respectively. The cumulative incidences (% ± SE) of CCyR by 12 months, MMR by 18 months and MMR by 24 months were 42.6 ± 7.1, 26.5 ± 6.3 and 35.2 ± 6.9, respectively. The cumulative incidence of MMR in pediatric patients was inferior to that in adult cohort (P < 0.0001) (Figure 1). Progression to accelerated phase and blast crisis occurred in 2 patients each. The 10-year progression-free survival (PFS) and overall survival (OS) (% ± SE) were not significantly different between pediatric and adult cohorts (90.4 ± 4.7 vs. 93.0 ± 1.3, P= 0.533; 90.6 ± 4.7 vs. 94.3 ± 1.6, P= 0.176).The IS levels at 3 months among three different Sokal risk groups did not differ in pediatric CML. Patients achieving MMR in Sokal low-risk group of pediatric cohort were significantly lower than those of adult patients (P= 0.002) whereas the PFS and OS by Sokal risk group in pediatric and adult CML patients did not show statistical difference.ConclusionsThe molecular responses in pediatric CML patients receiving front-line imatinib therapy were inferior to those of adult cohort, but the PFS and OS did not differ between the two cohorts. The Sokal scores did not predict outcome in pediatric CML. [Display omitted] DisclosuresShih:Novartis (Taiwan) Co., Ltd.: Research Funding.