Philadelphia-positive Chronic Myeloid Leukemia Research Articles

MiR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia

Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients’ bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.

Prognostic and predictive implications of Sokal scoring system in newly diagnosed Chronic Myeloid Leukemia patients

Objective: To assess the predictive utility of the Sokal scoring system for determining disease prognosis in newly diagnosed patients with chronic myeloid leukemia (CML). Methodology: This comparative cross-sectional study was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from September 2021 to September 2022. The study included all newly diagnosed Philadelphia-positive chronic myeloid leukemia (CML) patients. Patients with CML in the accelerated and blast phases, as well as those with atypical CML, were excluded. Gender was considered as a qualitative variable of interest, while platelet count, spleen size, age, and percentage of myeloblasts in the peripheral blood were the quantitative variables of interest. These variables were documented using preformed data sheets, and the prognostic class of each patient was recorded. Follow-up assessments were conducted after 3 months for patients who received the same tyrosine kinase inhibitor (TKI) therapy to avoid bias. Results: A total of 62 patients were included in the study, with a mean age of 46±5 years. According to the Sokal scoring system, 20 (32%) of 62 patients were classified as low-risk, 34 (54.8%) as intermediate-risk, and 8 (12.9%) as high-risk. Conclusion: The routine implication of traditional prognostic scoring systems, such as the Sokal score, is beneficial for stratifying CML patients into different risk groups due to its cost-effectiveness. Regression in Sokal score grades was observed after 3 months of TKI therapy.

The study of the impact of additional chromosomal aberrations and c-MYC and BCR::ABL1 genes amplification on CML patient’s characteristics: relation to haematological parameters and patient outcome

BackgroundChronic myeloid leukaemia is characterised by genetic instability which results in additional cytogenetic aberrations that have been linked to progression to advanced phase. Genomic study linked amplified genes in the form of c-MYC and/or the rare BCR::ABL1 genes amplification to chronic myeloid leukaemia. The effect of these genes’ amplification on patients’ characteristics and disease progression still needs further study.This cross-sectional study aimed to investigate the frequency of additional chromosomal aberrations in addition to c-MYC and BCR::ABL1 genes amplification in chronic myeloid leukaemia patients and their impact on patient’s characteristics, disease progression, and level of remission. The study included cytogenetic analysis of 49 Philadelphia positive chronic myeloid leukaemia patients and investigation of c-MYC and BCR::ABL1 genes amplification by fluorescence in situ hybridization.ResultsPatients with additional chromosomal aberrations represented 36.7% and had significantly lower platelet count (P = 0.003) and higher blast count (P = 0.008). The acquisition of additional chromosomal aberrations was significantly higher in chronic myeloid leukaemia patients with advanced stages (P = 0.014). Follow-up of the patients for 6 months revealed significant higher frequency of additional chromosomal aberrations in patients with failure of remission (P < 0.0001). A highly significant association between cases with failure of molecular remission (P = 0.001) and co-existing additional chromosomal aberrations.Amplification of the c-MYC gene was detected in 6 cases. The cases with c-MYC amplification showed significantly higher peripheral blood and bone marrow blasts (P = 0.029 and P = 0.008, respectively) and significantly lower platelet count (P = 0.044). Amplification of c-MYC was significantly associated with additional chromosomal aberrations (P = 0.011). Molecular remission was not achieved in any of the instances with c-MYC amplification. A highly significant association between c-MYC amplification and poor patient outcome was detected (P = 0.002). BCR::ABL1 amplification was detected in three cases, and ABL amplification was detected in four cases. Patients with BCR::ABL1 amplification showed significantly higher blast count. BCR::ABL1 amplification was significantly associated with disease progression and failure of molecular remission (P = 0.002).ConclusionAdditional chromosomal aberrations, c-MYC amplification, and BCR:ABL1 amplification in chronic myeloid leukaemia stratify patients with disease progression, which may lead to better interventions and improved outcome in the future chronic myeloid leukaemia patients.

Efficacy of Consolidation Therapy with Ponatinib 15mg on Treatment-Free Remission Rate in Patients with Chronic Myeloid Leukemia. Results of the Ponazero Trial

Introduction: Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has become part of routine clinical practice in recent years, thanks to growing evidence on their feasibility and safety. However, and despite adequate patient selection based on current recommendations, loss of response is observed in approximately 50% of patients. In this scenario, efforts are focused on finding strategies to increase the rate of successful discontinuations. Ponatinib has shown to induce deeper molecular responses compared with imatinib, but its risk of arterial occlusive events (AOE) limits its use in first line at its standard dose of 45mg. The risk of AOEs appears to be dose-related and following the results of the OPTIC study, dose reduction to 15mg in patients with good response is an increasingly popular strategy. Under these premises it has been postulated that a consolidation with ponatinib 15mg may increase the proportion of patients who could discontinue treatment successfully. Our aim is to evaluate the efficacy and safety of one year of consolidation therapy with ponatinib 15mg on treatment-free remission (TFR) rate in patients with CML who have achieved a deep molecular response with imatinib. Material and Methods: A multicenter open-label, single-arm, phase II, exploratory, prospective clinical trial (NCT 04043676) was conducted including patients with philadelphia-positive CML who met discontinuation criteria according to European LeukemiaNet recommendations, had received 4 years or more of imatinib therapy, with a documented grade 4 molecular response (MR4) at least 12 months prior to study entry. Uncontrolled arterial hypertension, active cardiovascular disease, or concomitant medication with potential for QTc prolongation were exclusion criteria. The study has two main phases: ponatinib consolidation (48 weeks), and ponatinib TFR phase (48 weeks); where patients remain without treatment. During the TFR phase, patients with a confirmed loss of MR4 or a single value above major molecular response (MMR) were scheduled to restart treatment with a TKI at investigator's discretion. The present abstract reports the results of the primary endpoint of the study; the proportion of patients with no loss of MR4 at the end of the TFR phase. Results: A total of 23 patients started treatment with ponatinib 15mg. One patient subsequently failed screening due to a major protocol deviation. Baseline patient characteristics were as follows: median age was 51.8 years (range 26-74), 65.2% were male. Ninety-five percent were Caucasian and 5% were Hispanic, ECOG was 0 in 83% and 1 in 17%, Sokal was low in 69.5%, intermediate in 17.5% and unknown in 13%. Eighteen patients were receiving imatinib 400mg daily (82%) at study entry, 2 patients 800mg and two 200mg. Median time on prior imatinib was 10 years (range 4-17), with a median time on MR4 of 3.6 years (range 1.9-13.3). Prior to initiation 13 patients (56.5%) had a grade 5 molecular response, 4 had a 4.5 molecular response (26%) and the remainder had a MR4. The adverse events (AEs) reported with ponatinib are summarized in Table 1, the most frequent being constipation (30%), asthenia (26%), myalgias and arthralgias (26% respectively) and skin rash (17%). A high rate of SARS-CoV2 infections was reported during the treatment period (26%), which should be interpreted considering that the study took place during the COVID-19 pandemic. Three patients out of 22 (13.6%) had serious AEs with ponatinib leading to treatment discontinuation; thrombophlebitis, erectile dysfunction, and intermittent claudication. Of the patients who entered the TFR phase, 14/19 (74%) continue with MMR without requiring treatment after a median follow-up of 12 months (68% with MR4) (table 1). Six patients (31%) lost MR4, five of them required reintroduction of an TKI (4 imatinib, 1 dasatinib; median time to reintroduction 5.4 months). All patients with MR4 loss were receiving the 400 mg dose of imatinib at study entry. All patients who restarted treatment recovered MMR. The sixth patient lost MR4 while maintaining an MMR without requiring treatment reinduction to date. Conclusions: Consolidation with 12 months of ponatinib 15mg in this study shows a high discontinuation success rate with an adequate safety profile, although not free of AEs. The results make this approach attractive for the design of further randomized clinical trials.

Abstract 4040: Asciminib activates erythroid differentiation in K562 cell line

Abstract Background: Asciminib an allosteric tyrosine kinase inhibitor (TKI) was recently approved by the FDA for managing Philadelphia positive chronic myeloid leukemia (CML) patients in chronic phase who had failed to respond to previous TKIs. In this study, we used human erythroleukemic K562 cell line to investigate the role of asciminib as an inducer of erythroid differentiation. Additionally, imatinib, which has previously been reported as a potential inducer of erythroid differentiation, was also tested on these cells, both independently as well as in combination, in order to investigate the degree of erythroid differentiation in a K562 cell line. Methodology: In this study, we investigated the effect of asciminib (5-20nM) with and without imatinib (50-200nM) in differentiating the erythroleukemic cell line K562 towards erythroid lineage. K562 cells were cultured over a 12-day period in basic (IMDM) media and an EPO-based differentiation media to select optimal medium conditions. In addition, an in-vitro drug cytotoxicity experiment (XTT) was used to determine the preliminary toxicity of asciminib with IMDM media and EPO-based differentiation media CD235a and CD71 surface marker expressions were analyzed by flow cytometry at all time-points to determine the degree of differentiation achieved by each of the conditions Moreover, to analyze and identify hemoglobin producing cells ensuing differentiation, benzidine staining was performed at indicated time points. Results: Our results suggest that asciminib, imatinib or a combination of both drugs in EPO-based differentiation media results in efficient erythroid differentiation with high levels of GPA expression (approx. 90%) and significant upregulation of globin genes (p value = 0.0001). These results were further confirmed by benzidine staining, where drug addition and dose escalation significantly increased benzidine-positive cells. Our results also demonstrated that asciminib was able to achieve maximum differentiation at a much earlier time point as compared to imatinib. Moreover, asciminib, when combined with another TKI such as imatinib, can also aid in lowering the drug concentrations being used, hence resulting in lessening the toxicity of the drug when used alone required at high doses. Conclusion: The results from this study highlighted the novel role of asciminib in erythroid differentiation using an in-vitro K562 model that can give high-levels of surface markers and globin expression. Potential clinical application of asciminib in hematological diseases that are associated specifically with a failure in the expression of globin genes should be evaluated. Keywords:K562, erythroid differentiation, asciminib, imatinib, glycophorin A, transferrin receptor, hemoglobin Citation Format: Hammad Hassan, Sarah Yousuf, Syed Muhammad Ahmed, Karim Ruknuddin, Hadiqa Raees, Sadia Habib, Fizza Iftikhar, Afsar Ali Mian, Elnasir Lalani. Asciminib activates erythroid differentiation in K562 cell line. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4040.

Evolution of Janus Kinase 2 V617F-negative idiopathic myelofibrosis into Philadelphia+ chronic myeloid leukemia

Limited data exist on the mechanisms promoting clonal expression of BCR-ABL1 cells in various myeloproliferative disorders. We present a patient whose Janus Kinase (JAK) 2 V617F-negative idiopathic myelofibrosis (IMF) transformed to Philadelphia-positive chronic myeloid leukemia (CML). A 55-year-old man had anemia and splenomegaly. Trephine biopsy showed excess fibrosis without a JAK2 V617F mutation. Diagnosis of high-risk IMF with t(3;12) and del(16q) was made. Five years later a repeated trephine biopsy showed extensive fibrosis and t(9;22) with der(22)t(9;22). BCR-ABL1 fusion gene with typical p210 fusion transcript was found resulting in the diagnosis of CML. A modest treatment response was achieved with tyrosine kinase inhibitor (TKI) therapies, but the disease eventually progressed to a myeloid blast phase. With AML-based chemotherapy plus azacytidine and a second generation TKI the patient survived for years but succumbed 11 years after the initial diagnosis. Clonal evolution may cause atypical disease characteristics or a poor response to targeted therapy in myeloproliferative disorders.

Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190BCR-ABL

BackgroundThe Philadelphia chromosome encodes the BCR-ABL fusion protein, which has two primary subtypes, P210 and P190. P210 and P190 cause Philadelphia-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), respectively. The Ph+ ALL is more malignant than Ph+ CML in disease phenotype and progression. This implies the key pathogenic molecules and regulatory mechanisms caused by BCR-ABL in two types of leukemia are different. It is reported that STAT6 was significantly activated only in P190 transformed cells. However, the potential role and the mechanism of STAT6 activation in Ph+ ALL and its activation mechanism by P190 are still unknown.MethodsThe protein and mRNA levels of STAT6, c-Myc, and other molecules were measured by western blot and quantitative real-time PCR. The STAT6 inhibitor AS1517499 was used to specifically inhibit p-STAT6. The effect of p-STAT6 inhibition on Ph+ CML and Ph+ ALL cells was identified by CCK-8 and FCM assay. Dual luciferase reporter and ChIP assay were performed to confirm the direct binding between STAT6 and c-Myc. The impact of STAT6 inhibition on tumor progression was detected in Ph+ CML and Ph+ ALL mouse models.ResultsOur results demonstrated that P210 induced CML-like disease, and P190 caused the more malignant ALL-like disease in mouse models. STAT6 was activated in P190 cell lines but not in P210 cell lines. Inhibition of STAT6 suppressed the malignancy of Ph+ ALL in vitro and in vivo, whereas it had little effect on Ph+ CML. We confirmed that p-STAT6 regulated the transcription of c-Myc, and STAT6 was phosphorylated by p-Jak2 in P190 cell lines, which accounted for the discrepant expression of p-STAT6 in P190 and P210 cell lines. STAT6 inhibition synergized with imatinib in Ph+ ALL cells.ConclusionsOur study suggests that STAT6 activation plays an essential role in the development of Ph+ ALL and may be a potential therapeutic target in Ph+ ALL.-58AP5UCfdMzXqQFXTpZyFVideo abstract

Efficacy and Safety of Vodobatinib in Patients (pts) with Chronic Phase Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML): A Sub Group Analysis By Lines of Tyrosine Kinase Inhibitor (TKI) Therapy

Efficacy and Safety of Vodobatinib in Patients (pts) with Chronic Phase Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML): A Sub Group Analysis By Lines of Tyrosine Kinase Inhibitor (TKI) Therapy

Evaluation of the combined effect of naringin and imatinib in philadelphia positive chronic myeloid leukemia

The combined effect of Naringin (NAR) and Imatinib mesylate (IMT) in Philadelphia positive chronic myeloid leukaemia was studied in vitro and in silico in this study. The chronic myeloid leukemia (CML) is a myeloproliferative hematopoietic cancer caused by a chromosomal translocation t (9;22). (q34; q11). IMT, a Tyrosine Kinase inhibitor that targets the BCR-ABL oncoprotein, is a first-line treatment for CML. IMT is related with the development of resistance due to mutation of Abl kinase domain. Natural compounds generated from plants have been linked to enhanced therapeutic efficacy and fewer adverse effects in cancer patients. Flavonoids, for example, are physiologically active substances with anti-cancer capabilities that influence a number of cellular signalling pathways suppressing a variety of malignancies. The primary goal of combining synthetic medications with phytochemicals is to achieve a therapeutic activity with the greatest pharmacological efficacy. Targeting AKT with flavonoid (NAR) compounds in conjunction with IMT treatment could be extremely beneficial in CML through additive processes. The combined effect of IMT and NAR in the treatment of CML was assessed using a silico molecular docking and long-term in vitro cytotoxicity assay on K562 cells.

Baseline blood count levels increase odds of cytopenia among CML patients in Kenya: a case control study

BackgroundImatinib is the gold standard for the treatment of all phases of Philadelphia positive Chronic Myeloid Leukemia (CML). During treatment, patients may develop cytopenia. We aimed to study the baseline characteristics and factors associated with cytopenia at a Nairobi Hospital.MethodsThis was a retrospective case-control study of patients aged ≥18 years on follow-up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. The cases consisted of CML patients on imatinib who developed cytopenia. The controls were CML patients on imatinib who did not develop cytopenia. Baseline socio – demographic, clinical, hematologic, and molecular data were retrieved from patients’ files. Chi square or fishers’ exact tests were used to analyze for differences between cytopenia and no cytopenia. Binary logistic regressions were employed to identify relationships. Univariate and multivariate analyses were done to identify independent predictors of cytopenia. Odds ratios (OR) were presented including the 95% confidence intervals and respective p values.ResultsA total of 201 patients were studied consisting of ninety-four (94) patients with cytopenia and 107 with no cytopenia. Among the entire population, males were 52, and 42% were aged 36–50 years. Sex, age, marital status, occupation and education level were similar between the cytopenia and no cytopenia groups.Among the 201 patients, 70% had symptoms for > 12 months before diagnosis, 78.6% had B symptoms at baseline, 80% had a moderate splenomegaly at baseline.Among patients with cytopenia, 40 and 37.4% developed cytopenia within 3 months and 3–6 months respectively after imatinib initiation. Baseline neutrophilia, neutropenia, anaemia, thrombocytosis, thrombocytopenia was found in 68, 11, 11, 23.5 and 11% respectively. Baseline hemoglobin, neutrophil and platelet level were significantly different between the cytopenia and the no cytopenia group. On univariable analysis, baseline anemia with hb < 7.9 g/dL (p = 0.002), neutropenia (p = 0.001), neutrophilia > 100,000/mm3 (p = 0.002) and thrombocytopenia (p = 0.001) increased the odds of developing cytopenia. On multivariable analysis, baseline anaemia (p value < 0.002), neutropenia (p value < 0.001), thrombocytopenia (p value, < 0.001) and thrombocytosis (p value, 0.033) increased the odds of developing cytopenia.ConclusionOdds of cytopenia were higher in presence of baseline cytopenia and thrombocytosis. Clinicians should have a high index of suspicion for these patients.

Transplant Outcomes in Patients with Ph+ Chronic Myeloid Leukemia: Haploidentical Donors Compared to Matched Sibling Donors and Matched/Mismatched Unrelated Donors: A Retrospective Analysis from the EBMT Chronic Malignancies Working Party (EBMT-CMWP)

Transplant Outcomes in Patients with Ph+ Chronic Myeloid Leukemia: Haploidentical Donors Compared to Matched Sibling Donors and Matched/Mismatched Unrelated Donors: A Retrospective Analysis from the EBMT Chronic Malignancies Working Party (EBMT-CMWP)

BILATERAL CHYLOTHORAX AND ANASARCA CAUSED BY DASATINIB IN A PATIENT WITH CHRONIC MYELOGENOUS LEUKEMIA

TOPIC: Disorders of the Pleura TYPE: Medical Student/Resident Case Reports INTRODUCTION: Dasatinib is one of the tyrosine kinase inhibitors that is used in the treatment for Philadelphia positive Chronic Myeloid Leukemia (CML). Pleural effusion can occur in 10% of patients on dasatinib, but chylothorax was rarely reported as a side effect of dasatinib (1,2). CASE PRESENTATION: A 52 year-old male with medical history of CML presented with shortness of breath over the past 4months. Patient was diagnosed with CML 10 years ago. Initially he was started on imatinib which he did not tolerate secondary to headache and he was switched to dasatinib 100mg daily which he tolerated for 5 years. Bone marrow biopsy showed complete cytogenetic remission in 6-months and he achieved major molecular remission. Physical exam was remarkable for reduced air entry to both lungs, abdominal ascites, and lower extremities pitting edema up to the groins. Basic labs were within normal limits. Chest X-ray showed bilateral pleural effusions and confluent bibasilar infiltrates. Computed topography of the chest showed large bilateral effusions with passive atelectasis in the lower lobes (figure-1A and 1B). CT scan of the abdomen and pelvis showed diffuse body edema in the lower abdomen extending to both lower extremities. Large right hydrocele and moderate left hydrocele were also noticed (figure-1C). Imaging guided thoracentesis was performed on the right side and 1900 ml of milky fluid was drained. Pleural fluid analysis showed total protein of 4.6 g/dL (serum total protein:7.3 g/dL), glucose of 97 mg/dL (serum glucose: 84 mg/dL), elevated lactate dehydrogenase (116 U/L), elevated triglyceride (485 mg/dL), and elevated cholesterol (83 mg/dL). Based on that, Diagnosis of chylothorax was made and dasatinib was discontinued. Patient was started on short course of diuretics and oral prednisone. After one month of dasatinib discontinuation, patients SOB improved significantly. Abdominal and lower extremities swelling has improved too. Repeated CXR showed improved bilateral pleural effusion (figure-1D). We kept patient off dasatinib with monthly check of BCR/ABL by PCR with plan to restart dasatinib at 50 mg daily or switching to another treatment if he relapses. DISCUSSION: Pleural effusion is a known side effect of dasatinib and few reports of unilateral chylothorax have been reported. Bilateral chylothorax and anasarca are very rare side effects of dasatinib. In most of the cases, discontinuation of dasatinib can improve symptoms. In a previous case report, 63 year-old female presented with right sided dasatinib induced chylothorax which totally resolved after switching dasatinib to nilotinib (2). In another case report, the 71 year-old patient presented with dasatinib induced chylothorax that initially resolved and then recurred after re-initiation of dasatininb (3). CONCLUSIONS: Bilateral chylothorax after dasatinib is very rare. Most cases resolve completely with dasatinib discontinuation. REFERENCE #1: Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. doi: 10.1056/NEJMoa1002315. Epub 2010 Jun 5. PMID: 20525995. REFERENCE #2: Al-Abcha A, Iftikhar MH, Abu Rous F, et al. Chylothorax: complication attributed to dasatinib use. BMJ Case Rep. 2019 Dec 16;12(12):e231653. doi: 10.1136/bcr-2019-231653. PMID: 31848139; PMCID: PMC6936595. REFERENCE #3: Chen B, Wu Z, Wang Q, et al. Dasatinib-induced chylothorax: report of a case and review of the literature. Invest New Drugs. 2020 Oct;38(5):1627-1632. doi: 10.1007/s10637-020-00932-3. Epub 2020 Apr 4. PMID: 32248338. DISCLOSURES: No relevant relationships by hamed daw, source=Web Response No relevant relationships by Christopher Haddad, source=Web Response No relevant relationships by Tariq Kewan, source=Web Response No relevant relationships by Talha Saleem, source=Web Response

CML-307: Assessment of 5-Year OS and Treatment Options in Newly Diagnosed Ph + CML Patients in the Republic of Armenia

Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the BCR-ABL1 mutation, resulting from the t(9; 22) (q22; q11) chromosome translocation. In Western countries, the median age at diagnosis of CML is 56–57 years. Treatment with tyrosine kinase inhibitors (TKIs) increases the number of patients with chronic phase (CP) and prolongs overall survival (OS). Compared to the early 1990s, in 2020, globally, TKI provided 91% of the median 5-year OS and 83% of the median 10-year OS. Our purpose is to show the 5-year OS rate during 2010–2015 in the Republic of Armenia (RA) and describe the treatment options and median age at diagnosis during 2010–2020. The data presented for this retrospective analysis was taken from the Armenian CML Register and the Register of Blood Diseases of the Hematology Center aft. Prof. R. Yeolyan. This information has been supplemented by data from the National Oncological Center after V.A. Fanarjyan, as well as data from the death registration service at the Ministry of Justice RA. The number of primary patients with Ph+ CML in 2010–2020 was 192, 100% of whom received TKIs in RA. Armenia has received imatinib from the Max Foundation since 2003. Since nilotinib and ponatinib have only become available in RA starting in 2017, the 5-year OS is mainly linked to the effectiveness of imatinib. Of 192 patients, 88.2% were diagnosed with CP, 8.8% in the accelerated phase (AP), and 3% in the blast phase (BP). 182 patients (95%) received imatinib, of which 152 patients received imatinib at a dose of 400 mg/day, 30 patients at 600 mg/day, and 1 pediatric patient at 300 mg/day. 10 patients (5%) received hydroxycarbamide. 5-year OS for 2010–2015 is 92%. Despite the limited treatment and monitoring opportunities and the younger median age at diagnosis, the 5-year OS rate in Armenia during 2010–2015 is similar to international statistics.

Several different cytogenetic clones arising during treatment of Philadelphia positive chronic myeloid leukemia with tyrosine kinase inhibitors lead to the progression into Philadelphia negative acute myeloid leukemia

Introduction. Additional karyotype abnormalities in the Philadelphia-positive (Ph+) clone can emerge during the progression of chronic myeloid leukemia (CML) and are of-ten associated with the resistance to treatment with tyrosine kinase inhibitors (TKI). Sometimes, during the TKI treatment, karyotype abnormalities can appear in the Philadelphia-negative (Ph-) cells as well but do not seem to adversely affect the outcome except for chromosome 7 abnormalities. Case report. The patient presented was in the chronic phase of Ph+ CML with highly diverse karyotype abnormalities. The abnormalities appeared in three unrelated clones during the TKIs treatment, followed by the evolution of the disease into acute myeloid leukemia (AML). The primary Ph+ clone was revealed during the chronic phase of CML, and therapy with imatinib mesylate was commenced. After a three-year hematologic and cytogenetic remission period, the evolution of the primary clone was noticed. Nilotinib was introduced, leading to a good molecular response and the disappearance/loss of the Ph+ clone with additional abnormalities but with the appearance of the Ph-clone with trisomy 8. Finally, after 5.5 years of nilotinib therapy, the Ph-clone with monosomy 7 occurred during the deep molecular response for BCR-ABL. At that time, the FISH analysis for trisomy 8 was negative, but the rise in blast count was noticed in the bone marrow, and the diagnosis of the secondary AML was established soon after. Conclusion. The achievement of the deep molecular response in CML patients does not rule out regular cytogenetic testing of their bone marrow. This is of crucial importance for detecting adverse karyotype abnormalities leading to the development of the myelodysplastic syndrome and AML.

Myeloid Blast Crisis of Philadelphia Positive Chronic Myeloid Leukemia and Philadelphia Positive Acute Myeloid Leukemia Treated at the AP-HP in Paris: A Retrospective Analysis

Myeloid Blast Crisis of Philadelphia Positive Chronic Myeloid Leukemia and Philadelphia Positive Acute Myeloid Leukemia Treated at the AP-HP in Paris: A Retrospective Analysis

Treatment-Free Remission in Chronic Myeloid Leukemia Harboring Atypical BCR-ABL1 Transcripts.

Discontinuation of tyrosine kinase inhibitors (TKI) is the main goal today in the field of Philadelphia positive chronic myeloid leukemia (Ph + CML) and the criteria to attempt the interruption of therapy are well defined and rely on the possibility to regularly monitor the BCR-ABL1 transcript. Patients harboring atypical transcripts are automatically excluded from protocols due to the absence of a standardized method of quantification of their minimal residual disease (MRD). We report here the outcome of 6 patients with atypical transcripts with a long follow up whose MRD was followed in three cases with digital PCR during their treatment free remission (TFR).

Cytopenia among CML Patients on Imatinib in Kenya: Types, Grades, and Time Course.

Background Imatinib mesylate is the gold standard for the treatment of all phases of Philadelphia-positive chronic myeloid leukemia. Patients on imatinib treatment may develop cytopenia due to drug toxicity. This study aimed to determine the types, grades, and time course of cytopenia in CML patients on imatinib at a Nairobi hospital. Methods This was a cross-sectional descriptive study of adult patients aged ≥18 years followed up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. Patients who developed cytopenia within 12 months of initiating imatinib were eligible. Clinical and hematologic data were retrieved from the patients' charts and entered into a study proforma. Measures of central tendency such as mean, median, mode, standard deviation, and variance were used for analysis. Results Sixty three percent (63.6%) of the 94 patients developed a monocytopenia, with anemia seen in 34%, neutropenia in 27.6%, and thrombocytopenia in 8% of the 94 patients. Anemia plus neutropenia was the most common bicytopenia at 12.7%. Pancytopenia was seen in only 5 of the 94 patients. Most of the cytopenia was grades 2 and 3. Anemia was present at baseline while neutropenia and thrombocytopenia developed within 12 months of imatinib initiation. Anemia resolved during the first 12 months of therapy while neutropenia and thrombocytopenia resolved within 24–36 months of treatment. Conclusion Monocytopenia, especially anemia, was the most common type of cytopenia. The cytopenia was predominantly grade 2, developed in majority of the patients within 6 months after imatinib initiation, and had resolved by 24–36 months after imatinib initiation.

Blue nails in chronic myeloid leukemia - Is it usual?

Nail toxicity is an uncommon cutaneous adverse effect of imatinib mesylate. Here, we have described a 45-year-old female, a diagnosed case of Philadelphia positive chronic myeloid leukemia, who was on imatinib mesylate for the past 3 months and developed bluish discoloration of the nails. This discoloration was related to the drug imatinib mesylate because the patient was only on imatinib and thyroxine medication. No any other skin-related diseases was present, which can lead to her nail changes.

Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia.

Objective:To determine the frequency of additional chromosomal abnormalities in Philadelphia chromosome positive Chronic Myeloid Leukemia (CML) by conventional cytogenetic analysis.Methods:This descriptive cross sectional study was conducted at Armed Forces Institute of Pathology (AFIP), Rawalpindi, from January 2012 to December 2016. A total number of 528 newly diagnosed CML patients were included in the study. The subjects were tested for the presence of Philadelphia (Ph) chromosome and other additional cytogenetic abnormalities by conventional cytogenetic analysis interpreted according to International System of Human Cytogenetic Nomenclature (ISCN) criteria. Molecular analysis for BCR-ABL was also performed for each patient. The additional cytogenetic abnormalities were then classified into major route abnormalities and minor route abnormalities.Results:Out of the 528 newly diagnosed CML patients, 378 (71.6%) were males and 150 (28.4%) were females. The age of patients ranged between 18 to 74 years. Four hundred and ninety-eight (94.3%) patients showed Philadelphia chromosome on karyotyping while 30 (5.7%) were negative for the Philadelphia chromosome. On analysis of these 498 Philadelphia positive patients, additional cytogenetic aberrations were detected in 26 (4.9%) patients. Of these, 7 (1.3%) had major route abnormalities while 19 (3.6%) had minor route abnormalities.Conclusion:The frequency of additional chromosomal abnormalities in our study were not in accordance with previous local and international studies.

Multicenter, Open-Label, Single Arm, Phase II Exploratory Study to Evaluate the Effect of a One-Year Consolidation Treatment with Ponatinib 15 Mg on Treatment Free-Remission Rate in Patients with Philadelphia-Positive Chronic Myeloid Leukemia, Who Had Previously Achieved a Deep Molecular Response with Imatinib (PonaZero_study)

Study Rationale The present study with ponatinib is based on previous studies on the potential role of imatinib discontinuation, to achieve a stable treatment-free remission (TFR) of patients with Philadelphia-positive Chronic Myeloid Leukemia (CML). As ponatinib has shown to induce deeper molecular responses compared with imatinib, the rationale is that ponatinib treatment could increase the proportion of patients who could discontinue treatment successfully. Purpose The purpose is to determine the successful TFR within the first 48 weeks following cessation of treatment in patients who achieved MR4 on imatinib, and maintained MR4 on ponatinib, after a switch from imatinib. Eligible patients have been previously treated with imatinib as unique tyrosine kinase inhibitor (TKI) therapy, for at least 4 years, and have documented MR4 (at least 12 months) at the time of ponatinib to study entry. Objectives The Primary Objective is to evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR (do not require confirmation). The Key Secondary Objectives are: To evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR within 72 and 96 weeks following ponatinib cessation.To estimate progression-free survival (PFS) from the date of ponatinib cessation to the date of the earliest event. Treatment-free survival (TFS) defined as a lack of any of the following: loss of MMR, confirmed loss of MR4, re-start of imatinib treatment, progression of AP/BP, or death from any cause.Overall survival (OS), defined as the time from the date of cessation of ponatinib therapy to the date of death from any cause.Proportion of patients who regain MR4 within 48 weeks of imatinib treatment re-initiation, following confirmed loss of MR4 within 48 weeks subsequent to ponatinib cessation.Kinetics of BCR-ABL transcript level (IS) after re-start of imatinib therapy. Other Secondary Objectives include adverse events, laboratory data for hematology, biochemistry, and urinary test, vital signs and ECGs. Exploratory Objectives include phenotypic and genotypic biomarkers, as well as functional analysis of cytotoxic cell activation. Plasma monitoring of ponatinib levels will also be performed. Study Design This is a single-arm, open label study, open label study in 40 patients who achieved and maintained MR4, to determine the rate of successful TFR in both gender patients, treated with 15 mg/day of ponatinb for 48 weeks. Ten Spanish sites will participate. The study has two main phases: ponatinib consolidation (48 weeks) and ponatinib TFR phase (96 weeks). Inclusion criteria are patients who had received a minimum of 4 years imatinib as unique TKI therapy, have documented MR4 at least 12 months prior to study entry, and will continue with MR4 before the discontinuation of ponatinib. After stopping ponatinb (TFR phase), BCR-ABL wil be monitored every 4 weeks during the first 48 weeks, and every 12 weeks during the last period of 48 weeks. Exclusion criteria include patients with transplant, atypical transcripts, CML treatment resistant mutation, or having cardiovascular or pancreatitis diseases. Figure 1: Current State of the Study First Visit First Patient: 17 JUL 2019 Patients Enrolled: 4 Patients Recruited: 3 Screening Failure: 0 In Screening: 1 patient Figure 1 Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. Steegmann:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.