Phase Chronic Myelogenous Leukemia Research Articles

Clinical Importance of Drug Adherence during Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia in Chronic Phase

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm constituting approximately 15% of newly diagnosed leukemia in adult patients. Development of tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with chronic CML in chronic phase. However, adverse drug events (ADEs) associated with TKI therapy have influenced drug adherence, resulting in adverse clinical outcomes and a decline in the quality of life (QoL). In this study, we carried out a unique questionnaire survey to evaluate ADEs, which comprised 14 adverse events. We compared drug adherence rates between patients using imatinib and those who switched from imatinib to nilotinib, a second-generation TKI. Following the switch, the total number of ADEs decreased considerably in most cases. Simultaneously, better QoL was observed in the nilotinib group than in the imatinib group. Drug adherence was measured using Morisky’s 9-item Medication Adherence Scale (MMAS). MMAS increased significantly after switching to nilotinib in all cases. Drug adherence is a critical factor for achieving molecular response in patients with CML. In fact, our results showed a strong inverse correlation between clinical outcome (international scale (IS)) and adherence (MMAS), with a stronger tendency in the nilotinib group than in the imatinib group. In conclusion, low occurrence of ADEs induced a high level of QoL and a good clinical response with second-generation TKI nilotinib treatment.

Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase

Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase

Expression Levels of JARID1B, Hes1 and MMP-9 Genes in CML Patients Treated with Imatinib Mesylate

To explore the relationship between the expression levels of JARID1B,Hes1 and MMP-9 genes and the stages of chronic myelogenous leukemia(CML) and the curative effect of imatinib mesylate (IM). Peripheral blood samples of 15 cases of CML in chronic phase and 10 cases of CML in progressive phase were collected from the Hematology Department of Taihe Hospital affiliated to Hubei University of Medicine and 15 cases of healthy people in the Physical Examination Center. CML patients were divided into effective group and ineffective group based on the efficacy after treatment with IM, then real-time PCR was used to detect the expression levels of JARID1B, Hes1 and MMP-9 mRNA, finally, the differences in the level of gene expression and their correlations with CML stages and IM curative efficacy were analysed. The expression levels of Hes1 and MMP-9 in initially diagnosed patients in chronic and progressive phase without IM treatment were significantly higher than those of health people（P＜0.05）. There was no significant difference in the expression level of JARID1B between chronic phase patients and health people（P＞0.05）, but the expression level of JARID1B in the progressive phase patients was higher than that of health people （P＜0.05）. The expression levels of JARID1B and Hes1 in the IM-effective group were not significantly different from those in the IM-ineffective group (P=0.85,P=0.82）, while the expression level of MMP-9 in the IM-effective group [JP2]was significantly lower than that in the IM-ineffective group（P＜0.05）. The expression levels of JARID1B Hes1 and MMP-9 relate with the different phase of CML; The expression levels of JARID1B and Hes1 have not significant relationship with IM curative efficacy, the MMP-9 gene expression level relates with IM curative efficacy.

Co-occurrence of t(8;21)(q22;q22) and t(9;22)(q34;q11) in a case with chronic myelogenous leukemia

To delineate laboratory and clinical characteristics of a case with chronic myelogenous leukemia (CML) and co-occurrence of t(9;22)(q34;q11) and t(8;21)(q22;q22). The patient was subjected to cytogenetic, molecular, morphological and immunophenotypic analyses. Cytogenetic analysis revealed presence of t(8;21)(q22;q22) in addition to t(9;22)(q34;q11) in the patient. Chimeric BCR/ABL and AML1/ETO genes were detected by fluorescence in situ hybridization (FISH). Transcripts of BCR/ABL210 and AML1/ETO fusion genes were detected by relative quantity PCR. Morphological study suggested that the patient was at the chronic phase of CML. No significant immunophenotypic abnormality was detected by flow cytometry. Co-occurrence of t(8;21)(q22;q22) and t(9;22)(q34;q11) is rare in CML. Only 5 similar cases have been described previously. This case suggested that chromosomal alterations may precede morphological, flow cytometric and clinical changes and accelerate progression of the disease.

Chronic myelogenous leukemia combined with solid malignant neoplasms: report of eight cases and review of literature

Objective To explore the clinical features of chronic myelogenous leukemia (CML) combined with solid malignant neoplasms. Methods The clinical data of 8 CML patients with solid malignant neoplasms who were admitted to the Affiliated Tumor Hospital of Zhengzhou University, the Central Hospital of Nanyang City, the First Affiliated Hospital of Science and Technology University of Henan, and the Central Hospital of Xinxiang City from August 2006 to August 2018 were analyzed retrospectively. The clinical features, treatment and prognosis of the patients were summarized with the review of literature. Results Among the 8 patients, 3 were male and 5 female, aged 40-76 years, with a median of 50 years old. Seven cases were in CML chronic phase, and 1 was in accelerated phase. Seven patients were treated with tyrosine kinase inhibitor (TKI), and only 1 patient was treated with hydroxyurea. In 8 patients, two cases presented with synchronous multiple primary cancer (SMPC), 6 cases presented with heterochrony multiple primary cancer (HMPC). two patients received the operation, 1 patient received the operation and chemotherapy, 4 patients received chemotherapy, and 1 patient received the isotope treatment. One SMPC patient died and another one was under treatment, and 6 HMPC patients were under treatment. Conclusions The relationship between CML and solid malignant neoplasm is under discussion, but patients with CML and solid malignant neoplasm are not unusual. Clinicians should raise awareness to avoid misdiagnosis. The treatment should follow the two main lines that are comprehensive treatment and individualized treatment. Key words: Leukemia, myelogenous, chronic; Neoplasms, multiple primary; Treatment; Prognosis

NOVEL-1st: Interim Analysis of a Non-Interventional, Multi-Center Observational Study to Assess the Safety and Efficacy of Nilotinib in Newly Diagnosed Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) in Taiwan

BackgroundThe selective tyrosine kinase inhibitor (TKI) nilotinib has been approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. The NOVEL-1st study was conducted to examine the long-term safety and efficacy of nilotinib in this group of patients in routine clinical practice in Taiwan.MethodsThe NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers across Taiwan between January 2013 and June 2016. The follow-up period was 36 months. The primary objective was to collect long-term safety data on nilotinib. Secondary objectives were to evaluate the efficacy of nilotinib by clinical response, disease progression, and survival.ResultsThe median age of the enrolled patients was 49.7 (20.2-89.6) years of whom 58.3% were males. The median duration from CML diagnosis to study enrolment was 25.5 days. Of the 129 enrolled patients, 59 (45.7%) had completed the study, 29 (22.5%) had withdrawn from the study and other patients are still under follow up. The most common reasons included adverse events (AE) (n = 8), discontinuing nilotinib (n = 6), and death (n = 4). All 129 patients were included in the safety analysis, while 122 patients in whom molecular response data were collected were included in the efficacy assessment.At the time of data cut-off, a total of 1,278 AEs were reported by 120 (93.0%) patients, of which 140 (11.0%) AEs in 41 (34.2%) patients were serious and 499 (39.0%) AEs in 40 (33.3%) patients were drug-related. Non-hematological and hematological AEs were consistent with other reports, with no new safety signal detected. Common hematological AEs (incidence ≥ 10 %) included thrombocytopenia (29.5%), anemia (19.4%), and leukopenia (14.0%). Frequent non-hematological AEs (incidence ≥ 10 %) included rash (21.7%), upper respiratory tract infection (19.4%), pruritus (18.6%), cough (17.1%), constipation (14.7%), diarrhea (12.4%), increased alanine aminotransferase (11.6%), increased bilirubin (10.1%), and insomnia (10.1%). Compared to previous studies, we observed lower rates of cardio- or cerebrovascular events (1.6%), fluid retention (2.3%), and hyperglycemia (2.3%) of all grades, but a higher rate of hepatotoxicity (20.9%) was seen in the study population. Five (3.9%) patients expired during the study of whom 2 were due to CML progression.The efficacy outcomes were comparable to other first-line studies of nilotinib. From 3 to 36 months, the rates of clinical response increased over time, from 67.4% to 91.5% for complete hematological response (CHR), 45.0% to 86.0% for complete cytogenetic response (CCyR), 15.5% to 79.1% for major molecular response (MMR), 3.9% to 56.6% for MR4.0 (BCR-ABL ≥ 4 log reduction), and 2.3% to 38.8% for MR4.5 (BCR-ABL ≥ 4.5 log reduction). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 88.7% of patients. MR4.0 and MR4.5 were significantly higher for patients with deeper EMR, confirming an association between early and long-term deep molecular response. To date, the median OS and PFS were not reached as death and disease progression were only observed in 5 and 2 patients, respectively.ConclusionsThe initial results of NOVEL-1st were comparable to other published first-line studies of nilotinib and demonstrated that nilotinib as a first-line treatment for Ph+ CML-CP patients was well-tolerated and efficacious in the real-world setting. Clinical response was observed as early as 3 months. Early molecular response is a potential predictor of long-term clinical outcome. The final analysis will be conducted when all patients have completed the study. DisclosuresNo relevant conflicts of interest to declare.

DUXAP10 regulates proliferation and apoptosis of chronic myeloid leukemia via PTEN pathway.

To investigate the role of DUXAP10 in chronic myelogenous leukemia (CML) and its underlying mechanism. We detected DUXAP10 expression in 82 CML patients, 12 normal controls, and CML cell line by qRT-PCR (quantitative real-time polymerase chain reaction). After transfection of si-DUXAP10 or si-PTEN in CML cell lines (K652, KG-1), we detected proliferation, cell cycle, and apoptosis by CCK-8 (cell counting kit-8), colony formation assay, and flow cytometry, respectively. Finally, protein expressions of p21, CDK2, Bcl-2, Bax, and PTEN were detected by Western blot. DUXAP10 was upregulated in CML tissues and cells, which was gradually increased in the chronic phase (CP), acceleration phase (AP), and blast phase (BP) of CML. Knockdown of DUXAP10 in K652 and KG-1 cells can remarkably inhibit cell proliferation, promote cycle arrest and apoptosis. Western blot and flow cytometry results demonstrated that DUXAP10 can reduce apoptosis by inhibiting PTEN expression. Overexpressed DUXAP10 accelerates the development and progression of CML by promoting cell proliferation, reducing cell cycle arrest and apoptosis via inhibiting PTEN expression.

Clinical observation of domestic generic imatinib for newly diagnosed chronic myelogenous leukemia in chronic phase

目的 观察国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期（CML-CP）的效果及安全性。 方法 回顾性分析东莞市人民医院2014年10月至2016年10月收治的23例年龄>18岁、初次确诊、除羟基脲外未接受其他任何抗CML治疗的CML-CP患者临床资料，所有患者均接受国产甲磺酸伊马替尼400 mg/次，1次/d口服治疗，评价3、6、12个月时的血液学、分子生物学反应及安全性。 结果 23例患者治疗后均达到血液学完全缓解。在可评估的20例患者中，在3个月时15例bcr-abl国际标准化（IS）值<10%；治疗6个月时16例达bcr-abl<1%；治疗12个月时8例bcr-abl<0.1%。不良反应均可耐受。 结论 国产甲磺酸伊马替尼治疗初诊CML-CP疗效可靠，不良反应可耐受。

Prognostic Implications of Derivative Chromosome 9 Deletions in Patients with Advanced-Stage Chronic Myelogenous Leukemia.

Elucidation of cryptic BCR/ABL1 gene rearrangement is exceptionally important in the clinical diagnosis and prognosis of chronic myelogenous leukemia (CML). Previous reports indicated an adverse prognostic effect of atypical BCR/ABL1 gene rearrangements with submicroscopic ABL1-BCR deletions on derivative chromosome 9 [der(9)] in CML patients. Dual color dual fusion locus-specific BCR/ABL1 fluorescent in situ hybridization (FISH) analysis together with G-banding using trypsin and Giemsa (GTG banding) was performed in 489 patients at different stages of CML to investigate the spectrum of BCR/ABL1 gene rearrangements. Among the study group analyzed, a significantly higher frequency of BCR/ABL1 gene rearrangements that is consistent with der(9) deletion were observed in the blast crisis (BC) phase at 41.67%, followed by the accelerated phase (AP) at 36.84%, the imatinib mesylate (IM)-resistant chronic phase (CP) at 23.08%, and the lowest incidence was found in de novo CP at 16.61%. 1R1G1F (1 red, 1 green, 1 fusion) with concurrent loss of ABL1-BCR fusion gene on der(9) chromosome was the major signal pattern identified in each group. The results from the current study show that this unusual BCR/ABL1 gene rearrangement is one of the steering forces toward disease progression in CML. Patients in AP/BC of CML with der(9) deletion showed poor response to IM therapy; however, patients with der(9) deletion in the early phases of CML responded well to IM treatment. Therefore, the establishment of an atypical FISH signal pattern in CML is of paramount important because it is associated with adverse clinical prognostic implications in advanced stages of the disease.

Expression of SHP-1 mRNA in Patients with Myelogenous Leukemia and Its Clinical Significance

To investigate the expression and clinical significance of SHP-1 mRNA in patients with myelogenous leukemia. The SYBR Green-based qRT-PCR was used to assess SHP-1 mRNA levels in 54 patients with chronic myelogenous leukemia (CML), 30 cases of de novo acute myelogenous leukemia (AML) and 10 persons without malignancy as controls. The relative expression levels of SHP-1 mRNA in control group (CG), chronic phase CML (CP-CML) group, advanced phase of CML (including accelerated phase CML and blastic phase CML) group and AML group were 1.15±0.62, 4.96±1.76, 2.60±0.90 and 0.45±0.20, respectively. The expression of SHP-1 mRNA in patients with CML significantly increased in comparison with that in CG(P<0.05). Meanwhile, the expression of SHP-1 mRNA in CP-CML group very significantly increased as compared with that in advanced stage of CML group(P<0.0001). The expression of SHP-1 mRNA in AML group significantly decreased as compared with that in CG group(P=0.0442). In CP-CML group, statistical analysis showed that SHP-1 mRNA expression at baseline in optimal responders (5.712±0.4476) was significantly higher than that in the suboptimal or failed responders (4.044±0.3701)(P=0.0090). Meanwhile, the SHP-1 mRNA expression in AML patients was higher than that in CR group (0.4984±0.05164) and non-CR group (0.3537±0.02388)(P=0.0017). The SHP-1 mRNA levels in CML patients are higher than that in AML patients, and probably correlats with disease progression of CML. The mRNA expression level of SHP-1 may be a molecular marker to predict early response to inatinib treatment in CP-CML and AML.

Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low-dose methotrexate therapy for rheumatoid arthritis and expressing two AML1/MDS1/EVI1 fusion proteins: A case report

The t(3;21)(q26.2;q22) translocation is a rare chromosomal abnormality exhibited almost exclusively in therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) or in the blastic crisis phase of chronic myelogenous leukemia, which results in the fusion of the runt related transcription factor 1 (RUNX1, also called AML1) gene at 21q22 to the myelodysplasia syndrome 1 (MDS1)-ecotropic virus integration site 1 (EVI1) complex locus (MECOM) at 3q26.2, generating various fusion transcripts, including AML1/MDS1/EVI1 (AME). The present study examined the case of an 84-year-old Japanese woman who developed t-MDS/AML with t(3;21)(q26.2;q22) subsequent to receiving low-dose methotrexate (MTX) treatment for rheumatoid arthritis. Following treatment with MTX for 6 years, the patient developed anemia and neutropenia, and MTX was discontinued. A total of 3 years later, the patient was diagnosed with MDS with t(3;21)(q26.2;q22) and del (5q), which progressed rapidly to AML within 3 months. The patients was subsequently treated with azacitidine and cytarabine chemotherapy, but succumbed to the disease 6 months after diagnosis. Sequencing analysis of the nested reverse transcription-PCR products from the leukemic cells revealed the expression of two types of alternatively-spliced AME transcripts with or without RUNX1 exon 6 sequences. Western blot analysis of the leukemic cells of the patient additionally revealed that the corresponding AME fusion protein products were expressed at high levels, and that these cells also prominently expressed CCAAT/enhancer-binding protein α, the repression of which has been reported to be involved in leukemogenesis mediated by AME. To the best of our knowledge, the case discussed in the present study represents the first report of MDS/AML with t(3;21)(q26.2;q22) developing following low-dose MTX therapy for rheumatoid arthritis. Nonetheless, the clinical and molecular features of the patient in the present study were representative of those patients who typically develop this disease following exposure to chemotherapy or radiotherapy for primary malignancy, which implicates MTX in the pathogenesis of t-MDS/AML. Moreover, we confirmed the expression of two AME fusion proteins for the first time in primary leukemic cells and analyzed several cellular factors implicated in AME-mediated leukemogenesis to gain some insight into its molecular mechanisms.

Is Going for Cure in CML Targeting Aberrant Glycogen Synthase Kinase 3β?

Chronic Myelogenous Leukemia (CML)-initiating cells (CICs) express the hybrid oncoprotein BCR-ABL at the highest levels compared to their differentiated progeny but fail to expand at the same rate as downstream leukemic myeloid cells. Moreover, the primitive stem cell clone that originates the indolent CML chronic phase (CP) remains almost invariant as the disease evolves to a fatal blast crisis (BC). Compared to their healthy counterpart, the most dormant BCR-ABL+ CICs show the tendency to remain in a somewhat unusual 'proliferative quiescence', i.e. a prolonged low-energy viable state that restrains the frequency of symmetrical (self-renewing) cell divisions while enforcing cell cycle entry and myeloid commitment under cytokine support. Over the past few years, we and others have proposed the nutrient-sensing protein serine/threonine kinase GSK3β. (glycogen synthase kinase 3β) as an attractive target to eradicate leukemia-initiating cells while sparing normal haematopoiesis. Beyond its natural negative effects on self-renewal, through the inhibitory phosphorylation of β-Catenin (Wnt signalling) and c-MYC (Hedgehog signalling), hyperactive GSK3β is reportedly crucial to link energy metabolism and nutrient availability to stem cell homeostasis processes. This review will integrate current evidence pertaining to the biological relevance of GSK3β in normal and malignant haematopoiesis, with particular emphasis on its role(s) at the CML CP stage and BC transformation. Preclinical evidence earmarking the use of novel small-molecule inhibitors of GSK3β as promsing anti-leukemia agents are also discussed.

Early efficacy observation of generic imatinib for treatment of chronic myeloid leukemia in chronic phase

Objective To evaluate the cytogenetic, molecular responses and safety of generic imatinib in newly diagnosed patients with chronic myelogenous leukemia in chronic phase (CML-CP) in 1-year at different stages. Methods From January 2014 to November 2014, 50 CML-CP patients received oral generic imatinib 400 mg/d. The cytogenetic examinations, bcr-abl transcript levels and safety were monitored after 3, 6, 9 and 12 months respectively. Results 46 of 50 patients insisted on oral generic imatinib and followed up 1 year. At 3-month, 52.0 % (26/50) patients reached the complete hematologic responses(CHR) rate, and patients at least achieved minor cytogenetic response (mCyR) and bcr-ablIS≤10 % were 84.0 % (42/50) and 42.0 % (21/50). At 6-month, patients at least achieved part cytogenetic response (PCyR) and bcr-ablIS≤10 % were 73.5 % (36/49) and 59.2 % (29/49). At 12-month, patients achieved complete cytogenetic response (CCyR), bcr-ablIS≤1 % and bcr-ablIS≤0.1 % were 60.9 % (28/46), 63.1 % (29/46) and 45.7 % (21/46). The grade 3 leukopenia, thrombocytopenia and anemia rates were 34 % (17/50), 40 % (20/50) and 30 % (15/50), respectively. No grade 4 hematologic toxicity occurred. The common non-hematologic toxicities included edema [84 % (42/50)], nausea [46 % (40/50)], muscle pain [20 % (10/50)], rash [16 % (8/50)], and impaired liver function [8 % (4/50)]. Conclusion Generic imatinib has a favorable effect in treatment of patients with CML-CP, and without serious adverse reactions. Key words: Leukemia, myeloid, chronic; Cytogenetics; Bcr-abl; Generic imatinib

A Novel Prognostic Factor for Allogeneic Hematopoietic Stem Cell Transplantation Based on Bone Marrow Assessment on the Day of Stem Cell Transplantation

[Introduction] Many factors predicting the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) recipient have been reported so far and widely used to assess the potential risk of undergoing allogeneic HSCT. Residual disease is considered one of the risk factors in HSCT, and mainly evaluated by bone marrow aspiration before HSCT. However, disease statuses at the point of stem cell infusion potentially differ from that of pre-transplant evaluation depending on the sensitivity for conditioning therapy or proliferation speed of the blast. In this study, we assessed residual disease by bone marrow aspiration on the day of stem cell transplantation (called "day 0" of HSCT) in order to analyze the relationship between day 0 marrow statuses and HSCT outcomes.[Methods] This study was designed as a retrospective observational analysis, and we collected the patients who received first allogeneic HSCT for hematological malignant diseases between 2010 and 2014. Extramedullary diseases were excluded from the analysis. All HSCTs were consecutive and performed in our center. Bone marrow aspirated material was examined histopathologically, and residual blasts were evaluated by specific markers by immunostaining. If it has detected residual blasts even if only a few cells, it was defined non complete remission (CR) on day 0 (abbreviated as "non-day0CR"). We divided the patients into two groups according to the existence of residual blast in bone marrow on day 0 of HSCT.[Results] We analyzed 121 HSCT recipients including 35 with acute lymphoblastic leukemia, 3 with acute undifferentiated leukemia, 65 with acute myeloid leukemia, 17 with refractory anemia with excess blasts and 1 with blast phase of chronic myelogenous leukemia. The median follow-up of survivors was 983 days (range 330 - 2092 days), and overall survival (OS) was 72% (95% confidence interval: 63 - 79%) at 1 year after HSCT. In univariate analyses, age higher than median 44 year-old, non-CR at the time of pre-HSCT assessment, hematopoietic cell transplantation specific comorbidity index (HCT-CI) at least 1 point, reduced intensity conditioning, and non-day0CR were extracted as predictors of poor OS. With multivariate analysis, HCT-CI and day 0 marrow status were significantly associated with OS. Furthermore, when patients were limited to pre-transplant non-CR subgroup, the patients achieving complete malignancies-free state on day 0 showed comparable prognosis with those who maintained CR before conditioning (Figure 1). Relapse after allogeneic HSCT was observed in 31 patients, and cumulative incidence of relapse was 11% (95% confidence interval: 6 - 17%) at 1 year after HSCT. With univariate and multivariate analyses, there were significant differences between the patients with CR marrow and those with residual malignancies on day 0 (P = 0.002). There was no significant difference in non-relapse mortality between the two groups (P = 0.18).[Conclusions] We showed that bone marrow status on day 0 was significantly associated with OS and cumulative incidence of relapse. To our knowledge, this is the first report about the association with day 0 marrow status and post-HSCT prognosis. A malignancies-free state on day 0 could predict favorable prognosis in allogeneic HSCT, and the patient with residual malignancies on day 0 had lower OS and higher relapse rate. For the patients with residual malignancies on day 0, rapid tapering of immunosuppressant or arrangement of scheduled donor lymphocyte infusion may improve the outcomes. [Display omitted] DisclosuresMiyamura:Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria.

A Single Center Retrospective Analysis of Adherence to Molecular Monitoring Guidelines in Patients with Chronic Myeloid Leukemia

Introduction In 2016, it is predicted that there will be 8,220 new cases of Chronic Myelogenous Leukemia (CML) in the United States, with an estimated 1,070 deaths from this disease (Siegel RL, et al, CA Cancer J Clin 2016, 66:7-30). Due to the prognostic significance of cytogenetic and molecular response to frontline Tyrosine Kinase Inhibitors (TKIs), expert panels such as the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) recommend strict guidelines to ensure adequate surveillance of patient's response to TKI therapy (Deininger M, et al, Blood 2009, 114: Abstract 1126). In this retrospective observational study, we studied adherence to current NCCN Guidelines in the management of CML. Methods Using both electronic and archived paper medical records, we identified 26 patients diagnosed with CML from 3/3/2003 to 12/9/2015 who were followed in a single community practice. Information at initial diagnosis regarding age, CML phase, spleen size, and initial TKI therapy selected were obtained. Monitoring parameters including frequency of follow-ups, complete blood counts, chromosomal analysis, molecular testing, and repeat bone marrow aspirates were reviewed. Evaluation for response to treatment with time to Complete Hematologic Response (CHR), time to Major Molecular Response (MMR), and time to Complete Molecular Response (CMR) were noted. Evaluations of treatment adherence and testing for BCR-ABL kinase mutations when milestones were missed or molecular progressions detected were recorded. Reasons for change in therapy and choice of subsequent treatment were also documented. Results The median age at diagnosis of CML was 53, with a male to female ratio of 1.6:1. In this group of 26 patients, only a single patient was diagnosed in the accelerated phase, the rest were in the chronic phase of CML. In 92%, clinical spleen size was logged. However, a single standardized method was not utilized which precluded calculation of Sokal scores for risk classification. In 88.5%, bone marrow aspirates were obtained to establish disease phase and enable bone marrow cytogenetic studies. Out of 26 patients, 16 (61.5%) were initially treated with imatinib, 6 (23%) were treated with dasatinib and 4 (15.4%) were treated with nilotinib. Attempts to achieve superior cytogenetic and deeper molecular response with dasatinib or nilotinib, coupled with lower rates of progression to advanced phases, were most frequently cited as reasons for choosing non-imatinib front line therapy. Only 50% of patients had complete compliance with periodic molecular testing at 3, 6 and 12 months during the first 2 years of diagnosis. The frequency of molecular and cytogenetic response assessments were often less than recommended. Only 2 of the patients studied underwent repeat bone marrow testing, with one enrolled in a clinical trial requiring periodic repeat bone marrow biopsies. The median time to achieve CHR was 27 days, median time to reach MMR was 26.5 weeks and median time to CMR was 7.9 months. Attempts to confirm patient compliance with oral TKI therapy were documented in 22 of the patients (84.6%). Three patients underwent testing for BCR-ABL kinase mutations at the time of molecular progression, however, none tested positive for resistance mutations. No patient had a hematological or cytogenetic relapse, and two patients switched from nilotinib to imatinib because of poor compliance due to toxicity. Conclusion Clinical practice guidelines promote evidence-based recommendations to guide clinicians in the management of CML. TKI therapy has evolved to be the primary treatment for chronic phase CML, and monitoring response to TKI therapy by setting cytogenetic and molecular milestones has improved quality of care and success with treatment. Unfortunately, real-world application of strict time lines for testing may not be feasible in all circumstances. Patient non-compliance with testing and marrow exams, interval illness and hospitalization, and errors in laboratory testing have served as barriers to adherence to NCCN guidelines. Despite a 50% compliance rate, there were no major untoward events (i.e. transformation to accelerated or blast phase) appreciated in this subset of patients. Disclosures No relevant conflicts of interest to declare.

MEF2C and CEBPA: Possible co-regulators in chronic myeloid leukemia disease progression

Chronic myelogenous leukemia (CML), a hematopoietic malignancy, characterized initially by a chronic phase (CP) progresses into blast crisis (BC) with the accumulation of secondary abnormalities. We have reported earlier that MEF2C, a target of miR-223, was significantly up regulated in CML and also showed a negative correlation with miR-223. In this study, gene expression arrays were used to identify the genes regulated by MEF2C during myelopoiesis. Statistical tools were used to understand the correlation between MEF2C and the targets in different phases of CML. Different CML cell lines and CML patient samples were treated with imatinib to study the effect of MEF2C on the target genes. We observed that MEF2C targets a set of myeloid genes including the myeloid transcription factor CEBPA. MEF2C and CEBPA expression patterns are negatively correlated in CML patient samples. We further show that the expression of MEF2C and CEBPA along with CSF3R is sufficient to molecularly classify different stages of CML. Imatinib, the drug of choice for CML, abrogates MEF2C expression and reverses CEBPA repression both in the cell line and the primary cells. We report the existence of a MEF2C and CEBPA correlation in CML disease progression.

Myeloid blast phase of chronic myelogenous leukemia, BCR-ABL1+, associated with a secondary translocation involving MLL: case report and review of the literature

Although secondary cytogenetic aberrations are frequent in myeloid blast phase (MBP) of chronic myelogenous leukemia, BCR-ABL1+ (CML), balanced translocations of the type that are recurrent in de novo acute myeloid leukemia (AML) are unusual in the setting of CML-MBP, and rearrangement of MLL as a secondary event in CML-MBP is extremely rare. We present a case of CML-MBP in which a translocation involving MLL was acquired as a secondary abnormality and review the relevant literature. The clinical, morphologic, immunophenotypic, and genetic findings were reviewed. A search of the relevant literature was performed. We report a case of CML presenting in MBP, in which a balanced translocation involving MLL was identified as a secondary cytogenetic aberration. The specific translocation seen in this case, t(3;11)(q21;q23), which is rare in de novo AML, has not to our knowledge been reported in the context of CML-MBP. Upon the completion of induction therapy, and attainment of morphologic remission of the acute leukemia, the secondary MLL translocation became undetectable, though BCR-ABL1 persisted. Although published examples are extremely rare, CML-MBP may be associated with secondary translocations involving MLL.

Preleukemic phase of chronic myelogenous leukemia: morphologic and immunohistochemical characterization of 7 cases

Patients with chronic myelogenous leukemia (CML) present typically with an elevated white blood cell count (WBC) and cytogenetic or molecular genetic evidence of t(9;22)/BCR-ABL1 fusion gene. Rarely, CML patients may present with a normal or mildly elevated WBC and are asymptomatic, and we describe 7 patients in this study. The WBC in these patients ranged from 3.6 to 14.3 K/mm(3) with 50% to 73% granulocytes and 0% blasts. In all patients, t(9;22)(q34;q11.2) was detected by conventional cytogenetics, and BCR-ABL1 fusion was shown, supporting the diagnosis of preleukemic CML (pre-CML). We compared these patients with a group of 5 cases of CML in chronic phase (CML-CP) and 5 bone marrow specimens with a leukemoid reaction (n=5). Reticulin, CD34, and CD61 immunostains were performed on all bone marrow biopsy specimens. Peripheral blood absolute basophilia (≥200/mm(3)) was noted in only 4 of 7 pre-CML cases, whereas it was present in all CML-CP cases and absent in leukemoid reaction cases. The mean ±SD of microvascular density of pre-CML cases (10.0 ± 4.3 vessels/200× field) was twice that of leukemoid reaction cases (5.0 ± 1.0) (P=.02; Student t test) but similar to that of CML-CP cases (12.5 ± 3.6). Microvessels in pre-CML, highlighted by CD34, were tortuous with abnormal branching, although to a lesser extent than those found in CML-CP. Microvessels in leukemoid reaction were generally straight. The percentage of small, hypolobated megakaryocytes, highlighted by CD61 in pre-CML, was 40%, 3 times that found in leukemoid reaction cases (13%) but less than that of CML-CP cases (86%). We conclude that pre-CML should be suspected in patients with a normal to mildly elevated WBC and absolute basophilia. Bone marrow examination can usually distinguish pre-CML from a leukemoid reaction based on the percentage of small, hypolobated megakaryocytes; microvascular density; and morphologic features.

Economic Impact of Imatinib Mesylate Withdraw: An Option for Third World Countries?

Introduction: The advent of tyrosine kinase inhibitors has changed the natural history of chronic myelogenous leukemia (CML), promoting molecular remission in a high number of patients. In 40-60% of the patients that reach deep molecular responses (RM4.5 or more) and are using imatinib mesylate for 24 months or longer, a molecular response can be maintained after the cessation of the drug. Besides improving life quality in those patients, to withdraw the medication could have a great economic impact in the health system, what is extremely important in third world countries.Objective: To estimate the economic impact of stopping imatinib mesylate in CML chronic phase patients, receiving treatment for at least 36 months and presenting deep molecular response, determinate by BCR-ABL transcripts with quantitative reverse transcriptase polymerase chain reaction (QRT-PCR), in the last 24 months.Patients and methods: A single center observational retrospective study, including all patients diagnosed with chronic phase CML, confirmed by cytogenetic or molecular exams receiving treatment at a tertiary hospital in Brazil. All patients received imatinib mesylate either in first or second line therapy. Patients presenting deep molecular response for at least 24 months, under imatinib mesylate for 36 months or more were considered eligible for discontinuation the drug. The annual coast with the treatment was estimated considering the coasts of the medication and the QRT-PCR molecular exams in the Brazilian public health system.Results: In this study, 169 patients date were analyzed, the median follow up time is 5 years (range 1-13 years), 26 (15%) of those patients are eligible for stopping imatinib mesylate according to the criteria previously mentioned. Considering the requirement of QRT-PCR exams every month in the first year of discotinuating the drug, these patients would coast proximally 1.550,00 dollars/ patients year for the public health system. This coast could be reduced to 800,00 and 520 dollars/patients year, after the second and third year of the medication withdraw, when monitoring molecular response can be done every 2 and 3 months respectively. The patients receiving imatinib mesylate, and having QTR-PCR exams every six months, in the other hand, would coast the Brazilian public health system over 31.000, 00dollars /patients year. Stopping imatinib mesylate could reduce CML chronic phase treatment coasts in up to 95%.Discussion: Discontinuating imatinib mesylate is something that must be done only in clinical trial. The economic impact projection shown in this study observed the eligibility criteria described in the literature. If stopping imatinib mesylate proves to be a safe option, studies promoting it should be done in Brazil and other third world countries, as a manner of saving resources in the health system. Furthermore, the impact in life quality free of adverse effects and the possibility of gestation in young woman is not to be ignored. DisclosuresNo relevant conflicts of interest to declare.

Abstract B38: F317i mutation-associated nilotinib resistance in a child with CML: A first report.

Abstract Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) accounts for only 2-2.5% of childhood leukemia cases or about 60 cases per year in the US. Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis and treatment of CML in adults and children. Failure of TKIs is often due to mutations. In adult CML, the F317i mutation has been implicated in resistance to first and second line TKIs (imatinib/dasatinib) without affecting sensitivity to the third line TKI, nilotinib. The F317i mutation has been documented a handful of times in adult CML and in childhood Ph+ALL cases. We describe what we believe to be a first report of F317i mutation in a child with Ph+ CML who, after initial major molecular responses, rapidly developed resistance to first, second and third line TKIs. The current Childrens Oncology Group trial of oral nilotinib (COG AAML1321) does not recognize F317i as a mutation associated with nilotinib resistance. Case: An 11-year old female with classic chronic phase (CP) CML was found to have the F317i mutation after initially achieving an MMR during the first 3 months of treatment while on dasatinib. After results of the F317i mutation were received, the patient was switched to nilotinib and again achieved an MMR in the first 2 months before rapidly decompensating with a pre B cell ALL blast crisis. The child was then treated with ALL induction and consolidation and allogeneic stem cell transplant and again achieved an MMR which has been sustained for 5 months. Methods: Cases of the F317i mutation have been documented in adults, however, we did an extensive literature search of PubMed, Ovid, and Google Scholar using keywords “F317” as well as F317i, ” and we were unable to find another report of this mutation in a child. Discussion: CML in children is rare and to our knowledge the F317i mutation in children has not been previously reported. In contrast to how the F317i mutation is expected to behave in adult Ph+ CML, our patient developed resistance to nilotinib. Conclusion: Our CML patient failed nilotinib. The F317i mutation in a child may warrant closer molecular monitoring and the consideration of early stem cell transplantation. Citation Format: Heidi Tucker, Paul Kent. F317i mutation-associated nilotinib resistance in a child with CML: A first report. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B38.