Treatment Of Chronic Myeloid Leukemia Patients Research Articles

Clinical applications of abnormal DNA methylation in chronic myeloid leukemia.

DNA methylation, a crucial biochemical process within the human body, fundamentally alters gene expression without modifying the DNA sequence, resulting in stable changes. The changes in DNA methylation are closely related to numerous biological processes including cellular proliferation and differentiation, embryonic development, and the occurrence of immune diseases and tumor. Specifically, abnormal DNA methylation plays a crucial role in the formation, progression, and prognosis of chronic myeloid leukemia (CML). Moreover, DNA methylation offers substantial potential for diagnosing and treating CML. Accordingly, understanding the precise mechanism of DNA methylation, particularly abnormal changes in the methylation of specific genes in CML, can potentially promote the development of novel targeted therapeutic strategies. Such strategies could transform into clinical practice, effectively aiding diagnosis and treatment of CML patients.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract: BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

KF1601, a Novel Orally Bioavailable Inhibitor of BCR-ABL1 T315I without Inducing Thrombotic Microangiopathy

Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib significantly reduces the mortality of CML patients with Bcr-Abl T315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-Abl WT and Bcr-Abl T315I with nanomolar IC 50 values; 2) KF1601 and ponatinib had similar potency in terms of inhibiting CRKL phosphorylation, which correlates to major molecular responses in CML patients. 3) In murine models using Ba/F3 Bcr-Abl T315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 4) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-Abl T315I mutation.

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.

BH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) was considered for a long time one of the most hostile leukemia that was incurable for most of the patients, predominantly due to the extreme resistance to chemotherapy. Part of the resistance to cell death (apoptosis) is the result of increased levels of anti-apoptotic and decreased levels of pro-apoptotic member of the BCL-2 family induced by the BCR-ABL1 oncoprotein. BCR-ABL1 is a constitutively active tyrosine kinase responsible for initiating multiple and oncogenic signaling pathways. With the development of specific BCR-ABL1 tyrosine kinase inhibitors (TKIs) CML became a much more tractable disease. Nevertheless, TKIs do not cure CML patients and a substantial number of them develop intolerance or become resistant to the treatment. Therefore, novel anti-cancer strategies must be developed to treat CML patients independently or in combination with TKIs. Here, we will discuss the mechanisms of BCR-ABL1-dependent and -independent resistance to TKIs and the use of BH3-mimetics as a potential tool to fight CML.

The role of CSE1L silencing in the regulation of proliferation and apoptosis via the AMPK/mTOR signaling pathway in chronic myeloid leukemia

ABSTRACTObjectivesChromosome segregation 1-like (CSE1L) is abundant and strongly expressed in solid tumors. However, the expression and role of CSE1L in chronic myeloid leukemia(CML) remain largely unknown.Materials and methodsThe relative expression levels of CSE1L in bone marrow granulocytes from patients with primary CML and non-hematologic controls were measured by flow cytometry. Cell counting kit-8 analysis, DNA Content Quantitation Assay, and Annexin V-PE/7-AAD staining were applied to assess the effects of CSE1L knockdown on cell proliferation, cell cycle progression, and apoptosis.ResultsElevated expression of CSE1L was detected in bone marrow granulocytes of patients with primary CML. In the CML cell line K562 cells, CSE1L knockdown impaired cell proliferation blocked the cell cycle shift from G0/G1 phase to the S phase, and promoted apoptosis. Knockdown of CSE1L reduced Bcl-2 protein expression and increased Bax protein expression. Meanwhile, knockdown of CSE1L enhanced the expression of phospho-AMPK protein and decreased the expression of phospho-mTOR protein. The expression of total AMPK and mTOR proteins was not affected. In addition, CSE1L expression levels were decreased in imatinib-treated K562 cells.ConclusionsCSE1L plays a pivotal role in K562 cell survival and growth. These functions may be partially dependent on the AMPK/mTOR signaling pathway to achieve. In addition, CSE1L may have had a future impact on the treatment of CML patients.

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%-40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

CML-125 Clinical Significance of Serum Prohibitin in Chronic Myeloid Leukemia Patients on First-Line Tyrosine Kinase Inhibitors

Prohibitin is a widely expressed intracellular protein that is distributed in various compartments, where they exert different biological functions accordingly. Prohibitins have displayed both pro-tumorigenic and antitumorigenic roles in cancer formation. Depending on the type of cancer and the localization of prohibitin, studies have shown that it exerts a different biological role. To investigate prohibitin level in Egyptian patients with chronic myeloid leukemia (CML) and to evaluate its correlation with disease activity and response to first-line tyrosine kinase inhibitor treatment. A case-control prospective study. Clinical Haematology division of Internal Medicine Department, Ain Shams University Hospitals. 80 CML patients in the chronic phase. They were matched to 10 healthy volunteers as a control group. Prohibitin level was measured using an enzyme-linked immunosorbent assay. We reported a significant value of prohibtin level in CML patients and a significant correlation between its level and disease activity and response to treatment. We have demonstrated that prohibitin levels were significantly higher in patients with CML than in the control participants (P=0.002). Prohibitin levels were significantly higher in CML patients with an active disease status (P=0.001). In addition, significantly higher levels of prohibitin in CML patients were associated with poor response to first-generation TKIs (P=0.001). A serum level of prohibitin higher than 289 is a good predictor of poor response to first-generation TKIs as per response assessment by PCR for BCR-ABL (area under the curve=0.67, sensitivity and specificity 58.33 and 80.56, respectively). Prohibitin is overexpressed in CML patients and has a possible impact on disease activity and response to treatment in CML patients that warrants further investigations.

Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety.

Development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective approach for the treatment of chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia. However, currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild type and mutant BCR-ABL kinase, including the “gatekeeper” T315I mutation that is resistant to all other currently available TKIs. However, it is one of the most cardiotoxic of the FDA-approved TKIs. Herein, we report the structure-guided design of a novel series of potent BCR-ABL inhibitors, particularly for the T315I mutation. Our drug design paradigm was coupled to iPSC–cardiomyocyte models. Systematic structure–activity relationship studies identified two compounds, 33a and 36a, that significantly inhibit the kinase activity of both native BCR-ABL and the T315I mutant. We have identified the most cardiac-safe TKIs reported to date, and they may be used to effectively treat CML patients with the T315I mutation.

OCT-1 Expression in Patients with Chronic Myeloid Leukemia: A Comparative Analysis with Respect to Response to Imatinib Treatment.

The introduction of tyrosine kinase inhibitors (TKI) has resulted in a significant improvement in the treatment of CML patients. However, some CML patients are resistant to imatinib therapy, the initial TKI therapy in the CML. Therefore, it is important to find prognostic markers for resistance. The OCT-1 gene involved in imatinib uptake is also suspected to cause imatinib resistance. The aim of this study was to investigate the role of OCT-1 in imatinib resistance by comparing OCT-1 expression levels in imatinib resistant and imatinib sensitive patients with chronic myeloid leukemia (CML). This study was conducted on 101 patients with CML [imatinib sensitive (n = 51) and imatinib resistant (n = 50)] who were treated with imatinib. Gene expression analysis was done using QRT-PCR. The relative expression levels of OCT-1 were calculated using 2(-ΔΔCT) method. OCT1 mRNA expression levels were 0.149 (0.011-2.532) and 0.119 (0.008-2.868) in imatinib-sensitive group and imatinib-resistant group, respectively. OCT-1 expression levels were not significantly different in the imatinib-sensitive group when compared to imatinib resistant group (p > 0.05). OCT-1 expression was also similar in BCR-ABL1 kinase domain mutation positive and negative cases (p > 0.05). The imatinib-resistant group had a higher rate of hydroxyurea or interferon-alpha treatment prior to imatinib therapy and a lower rate for first-line imatinib as the only treatment than the imatinib-sensitive group (p = 0.002 and p = 0.002, respectively). According to the results of our study, OCT-1 does not have a biomarker feature in the evaluation of imatinib response. In addition, the study should be performed in larger patient groups.

Pro-Inflammatory and Pro-Oxidative Changes During Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study).

Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an “inflammatory status” during nilotinib that may explain the increased incidence of AOEs. Thus, we conducted this prospective KIARO study involving 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib). Interleukin 6 (IL6), interleukin 10 (IL10), Tumor Necrosis Factor-α (TNFα), oxLDL, and high-sensitivity C-reactive protein (hs-CRP) plasma levels were measured at diagnosis and during treatment, with the aim to investigate changes in the inflammatory status favoring AOEs of each patient. Clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. We showed a pro-inflammatory/pro-oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher hs-CRP and oxLDL levels and increased IL6/IL10 and TNFα/IL10 ratios only in nilotinib cohort. After median follow-up of 23.3 months starting from TKI, 10/186 patients (5.4%) suffered an AOE. Approximately 5/10 (50%) AOEs occurred during nilotinib treatment despite a lower 10-year SCORE and a lower median age in this subgroup. A longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.

Priapism as the initial presentation in chronic myeloid leukemia is a red flag sign: A case report

Chronic myeloid leukemia (CML) is a myeloproliferative disorder of the hemopoietic stem cells, which may occasionally present with symptoms of leukostasis secondary to hyperleukocytosis, which includes headache, priapism, and dreaded ones such as stroke and myocardial infarction. This is a case of a 23-year-old man who presented with priapism and was subsequently found to have CML. The patient later developed stroke and succumbed to it. This case demonstrates that the importance of treating CML patients presenting with signs of hyperleukocytosis promptly and cautiously to prevent the impending grievous complications.

Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an “inflammatory status” during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs.Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status.Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated.Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients.After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082).Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. [Display omitted] DisclosuresAbruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

Regulation of miR-126 and miR-122 Expression and Response of Imatinib Treatment on Its Expression in Chronic Myeloid Leukemia Patients

Background: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. Methods: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. Results: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. Conclusion: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.

Abstract 1462: KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy

Abstract Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib is the only approved drug for Bcr-AblT315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-AblWT and Bcr-AblT315I with nanomolar IC50 values; 2) In xenograft models using Ba/F3 Bcr-AblT315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 3) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-AblT315I mutation. Citation Format: HyunJin Kwon, Sung-Min Ahn, Kiho Chang, WooSik Kim, Amir Khan, Doohyun LEE, Seungyeon Lee, Ye Ri Han, Chun Young Im. KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1462.

Imatinib (IM) in Combination with Hydroxyurea Showed Significantly Lower Major Molecular Response Rates at 6 Months but Similar MMR at 18 Months in Patients with CML1st CP Compared to IM Alone. Final Results of the CML2004 Study. NCT 02480608

Introduction: Imatinib (IM) monotherapy remains an important option to treat newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). Hydroxyurea (HU) is effective in controlling elevated white blood cell counts and was widely used to treat CML prior to the era of tyrosine kinase inhibitors (TKIs). After combinations of IM and HU showed additive effects on Ph+ cells in vitro the East German Study Group conducted a study in patients with CML first chronic phase.Methodes: Starting in 2002, 20 adult patients with newly diagnosed CP-CML were included in the phase I study to identify the dose of HU in combination with standard dose IM (400mg daily) that would result in mild myelosuppression (white blood cell count 3,000-4,000/mL). Starting dose of HU was 500mg daily increasing by 500mg every 3 weeks to a maximum of 3,000 mg daily. In line with the protocol, 500mg HU was chosen as the starting dose for the randomized phase II study which tested the combination vs. standard dose IM, with the rate of major molecular response (MMR) at 18 months as the primary endpoint.Additional 93 patients were enrolled in the phase II of the study, 5 of whom were excluded, leaving 88 patients to be randomized 2:1 to the IM/HU (n=59) and IM (n=29) arm, respectively. Three patients (2 IM/HU, 1IM) were lost to follow-up. As prospectively designed, IM/HU patients (n=77) from the phase I and II were analyzed in combination with patients from the CML study IV (n=49) selected by propensity score matching. The median age of the 154 patients was 55 years (range 18 - 82). The EUTOS long-term survival prognostic score was available for 141 patients and was high in 8 (5.7%), intermediate in 35 (24.8%) and low in 98 (69.5%), with no significant differences between treatment groups. The median HU dose was 500mg (range 152-3000); the median IM dose was 400 mg (range 145-617mg) in both arms.Results: The 5-year overall survival (OS) was 90.4% and 84,9% in the IM/HU and IM arm respectively (not significant). Similarly, progression-free survival (PFS) at 5 years amounted to 86.7% in the IM/HU and 84.9% in the IM arm.With IM/HU, the probabilities of complete cytogenetic response (CCR) at 6, 12, and 18 months were 54.3, 84.0, and 93.7%, respectively. In the IM arm, the corresponding numbers were 70.4, 84.9, and 83.3% (p=not significant).Molecular Response Rates (MMR) in the two arms were evaluated at 6 months with 21.6 (IM/HU) vs. 41.1% (IM) (p=0.0383) and at 12 months with 41.9 (IM/HU) vs. 58.9% (IM; not significant). The primary endpoint of the study (MMR rate at 18 months) did not significantly differ between the IM/HU (65.8%) and the IM (66.0%) arms.No significant differences were detected in time to event analyses of OS and PFS or in group comparisons between the probabilities of CCR and MMR.The gross numbers of adverse events in general or of adverse events of grade 4 were not different between the two arms. However, cumulative incidences showed an earlier occurrence in the IM/HU than in the IM arm (p= 0.0343, Gray test)Conclusion: Compared to Imatinib only, the combination of Imatinib and HU resulted in a lower MMR rate at 6 months but a similar MMR rate at 18 months. Furthermore, IM/HU was associated with more early adverse events. There was no indication of a beneficial effect in the treatment of CML patients in 1st chronic phase using the combination of IM with HU. DisclosuresLange:Novartis: Honoraria, Research Funding. Al-Ali:Gilead: Consultancy, Honoraria; Alexion: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Pfirrmann:Novartis: Honoraria; BMS: Honoraria. Hehlmann:Novartis: Research Funding; BMS: Consultancy. Deininger:Incyte: Consultancy; BMS: Consultancy, Research Funding; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; ARIAD: Consultancy; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Research Funding.

Higher Red Blood Cell Distribution Width is a Poor Prognostic Factor for Patients with Chronic Myeloid Leukemia.

PurposeRed blood cell distribution width (RDW) has been considered as a potential indicator of the effects of treatment or as a prognostic indicator for various malignancies. Most chronic myeloid leukemia (CML) patients are in the chronic phase, but some have transformed to accelerated phase or blast phase (blast crisis). However, the clinical significance of RDW in CML remains limited.Patients and MethodsIn the present study, detailed clinical information and the RDW of 168 healthy people and 153 CML patients (106 patients for the training cohort and 47 patients for the validation cohort) were retrospectively assessed.ResultsMultivariate analysis demonstrated that patient age (OR, 1.081; 95CI% 1.039~1.125; p < 0.001), platelet counts (OR, 0.997; 95CI% 0.994~0.999; p = 0.001) and RDW at admission (OR,1.469; 95CI% 1.121~1.925; p = 0.005) were significantly associated with the patients with advanced phase. Among CML patients in the chronic phase, higher RDW was significantly associated with overall survival (OS; p = 0.0008) and the event-free survival (EFS; p = 0.0221) among CML patients with chronic phase, but not with Transformation-free survival (TFS; p = 0.0821). Furthermore, higher RDW was associated with higher mortality compared to patients with low RDW (CML-associated deaths; p < 0.0001). In addition, a decline in RDW is associated with the treatment of CML patients with tyrosine kinase inhibitors, especially at 6 and 12 months after the start of treatment.ConclusionHigher RDW is a potential prognostic biomarker for chronic CML patients.

Target Inhibition of CBP Induced Cell Senescence in BCR-ABL- T315I Mutant Chronic Myeloid Leukemia.

The treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, has yielded clinical success. However, the direct targeting of BCR-ABL does not eradicate CML cells expressing mutant BCR-ABL, especially the T315I mutation in BCR-ABL. Moreover, increasing mutations were identified in BCR-ABL domain, resulting in TKIs resistance recently. It is necessary to find BCR-ABL-independent target for treating CML patients with various mutations, including T315I mutation in BCR-ABL. The dichotomous behavior of CREB binding protein (CBP) and E1A protein (p300), recruited by β-catenin associated with self-renewal and differentiation, have been identified in hematopoietic stem cells, respectively. In this study, CBP was aberrantly expressed in CML cells on the basis of Oncomine dataset. The β-catenin bound with much more CBP than p300 in CML cells. Down-regulation of CBP inhibited cell proliferation capacity and increased the binding of β-catenin to p300, thus promoting cell differentiation and p53-dependent cell senescence in CML cells with either wild type or T315I mutant BCR-ABL in vitro and in vivo models. These demonstrate CBP blockage can be developed for the treatment of CML independent of BCR-ABL mutation status including T315I.

Chronic myeloid leukemia: aiming for treatment free remission

BCR-ABL tyrosine kinase inhibitors (TKIs) dramatically improve the chronic myeloid leukemia (CML) prognosis, and most CML patients in the chronic phase are now able to lead lives that are comparable to those of healthy individuals. However, the high cost and adverse effects associated with long-term treatment remain issues in the treatment of CML patients. At the setout, a clinical study involving the discontinuation of imatinib was conducted in France. Thereafter, several TKI stop studies of first-generation (imatinib) and second-generation TKIs (dasatinib, nilotinib) have shown an earlier response than that with imatinib. These studies revealed that almost 50% of CML patients who were treated with TKIs and achieved a certain period of sustained deep molecular response can stop TKIs safely and obtain sustained treatment-free remission (TFR). Adverse effects of TKI withdrawal and predicting factors for successful discontinuation including immunity are gradually becoming clear via these studies. For superior CML treatment, several promising agents, including ABL001, are being developed. I trust that these efforts will enable CML patients to maintain TFR in the near future.

Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle

Pathogenesis of chronic myeloid leukemia (CML) has mostly been studied with regard to the oncogenic role of BCR/ABL fusion; however, recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored. Given the involvement of cyclin-dependent kinases (CDKs) in the pathogenesis of CML, the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells. Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27. The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity, suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor, at least partly, through a c-Mycdependent mechanism. To the best of our knowledge, to date, no study has addressed the effect of autophagy on CML cell response to AT7519, and, herein, we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562. Overall, we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.