Ph-positive Chronic Myeloid Leukemia Research Articles

Асциминиб у больных хроническим миелолейкозом, не имеющих альтернативных методов лечения: результаты исследования в рамках программы расширенного доступа МАР (Managed Access Program, NCT04360005) в России

Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia. Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model. Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs. Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.

Outcome of Philadelphia chromosome-positive chronic myeloid leukemia in the United States since the introduction of imatinib therapy-The Surveillance, Epidemiology, and End Results database, 2000-2019.

Since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) in 2000, the treatment of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) has improved significantly. This study aimed to evaluate Ph-positive CML outcomes in the TKI therapy era, considering factors like age, ethnicity, and income. Using the Surveillance, Epidemiology, and End Results (SEER) database, 2857 patients with Ph-positive CML diagnosed from 2000 to 2019 were analyzed. The overall 5-year survival rates in Ph-positive CML increased to above 80%, compared with pre-TKIs historical data reporting 5-year overall survival (OS) rates of less than 50%. The 5-year OS rate was 73% for patients diagnosed in 2000-2004, 82% in 2005-2009, and 78% in 2010-2014; the 4-year OS rate was 83% in 2015-2019. The 5-year OS rate for younger patients (<60years old) was 88% in 2000-2009 and 90% in 2010-2019 (p value .426). In older patients (60+ years old), the 5-year OS rates were 64% and 65%, respectively (p value, .303). Lower household income was associated with inferior survival across the 2000-2019. These results are inferior to European studies where TKIs are universally available and affordable, and relative OS in CML is similar to age-matched normal populations. Although the outcome of Ph-positive CML has improved significantly since 2000, the SEER data still shows differences in outcomes among patient subsets, some anticipated (worse OS in older patients accounted by the relative OS), but others that suggest less than universal access and affordability of this therapy (among poorer patients) in the United States.

Two-Year Updated Results of Asciminib Managed-Access Program (MAP) in Russia

Background: Asciminib is a Specifically Targeting the ABL Myristoyl Pocket (STAMP) ABL. kinase inhibitor that has shown efficacy and a good safety profile in clinical trials in patients with Ph-positive chronic myeloid leukemia (CML) failing prior TKI lines. It was confirmed by real world data in Novartis approved Managed Access Program (MAP) in several countries.Aim: to present two-year updated results of asciminib use in clinical practice in the MAP program in 3 centers of Russia. Methods: In total the data of 50 CML pts who received asciminib for more than 9 months and did not undergo bone marrow transplantation was analyzed. Pts recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. All pts had a chronic phase (CP) CML, 8 pts had a second CP after accelerated phase (n=7) or blast crisis (BC). Complete cytogenetic response (CCyR) corresponding to BCR::ABL1 ≤1%, major molecular response (MMR) and deep molecular response (MR4) achievement was assessed by cumulative incidence function (CIF) with Gray's test for comparison responses in subgroups. Survival analysis was performed by Kaplan-Meier method. Results: All pts were divided into two groups: 20 pts received an initial dose of 200 mg BID (19/20 pts with BCR::ABL1 T315I ), 30 pts received 40 mg BID (1/30 pts with BCR::ABL1 T315I ). Baseline characteristics of the two dose groups are presented in table 1. The median follow-up among all pts was 17 months (range 10-37); 7(14%) pts discontinued asciminib (5 due to resistance, 2 due to progression). Two-year survival rate without treatment discontinuation was 83%. The 2-year OS was 100% and 93% in 400 mg and 80 mg dose groups, respectively, two (4%) pts progressed to BC and died. CIF of CCyR, MMR and MR4 by 24 month was 55%, 29% and 17% for 80 mg dose and 45%, 48% and 45% for 400 mg dose respectively. There was no significant difference in response rates between the two dose groups. In the 400 mg dose group, the cumulative incidence of MMR was significantly higher in ponatinib-naive patients (75% vs. 23% in ponatinib-pretreated patients, p=0.006) (figure 1). Twenty two (44%) pts experienced any adverse events (AEs) and 8 (16%) had AEs of grade 3-4. AEs of grade 3-4 connected with asciminib included neutropenia, thrombocytopenia and irregular menstruation. No pts stopped treatment due to toxicity; no difference in toxicity was found between doses of 80 and 400 mg/day. Conclusion: Asciminib shows promising results for the treatment of highly pre-treated CML pts and should be considered as therapeutic options for pts with failure to previous TKIs. The 400 mg dose was well tolerated and highly effective in ponatinib-naive pts with BCR::ABL1 T315I and should be investigated in clinical trials in patients without T315I as a potentially more effective and well tolerated dose. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

Rare Case of Pericentric Inversion, Inv(9)(p13q34) of the Der(9)t(9;22)(q34;q11) in A Patient with Chronic Myeloid Leukemia – A Case Report

As we know, the Philadelphia chromosome (Ph) is a highly specific marker for chronic myeloid leukemia (CML). This hematological disease is characterised by the formation of the BCR/ABL1 fusion gene, usually with typical translocation pattern including 9q34 and 22q11. In this paper we describe a 55 years old female patient with typical clinical and haematological signs of CML and a chromosome 9 differing from that which normally participates in translocation t(9;22). The karyotype of this Ph positive patient is characterised by pericentric inv(9)(p13q34) of the der(9)t(9;22)(q34;q11). Reverse transcriptase-polymerase chain reaction revealed a e14a2 type of BCR/ABL1 fusion transcript. As a consequence of this unusual translocation, FISH also found the separation of the ABL1/BCR1 fusion gene on chromosome 9. On reviewing the literature, to date only 10 Ph-positive leukemia patients have been noticed to have pericentric inversion inv(9)(p22q34)der(9)t(9;22)(q34;q11). No one case has been described with pericentric inversion inv(9)(p13q34) of the der(9)t(9;22)(q34;q11). This indicate that pericentric inv(9)(p13q34) of the der(9)t(9;22)(q34;q11) is a novel, rare, chromosomal abnormality in Ph-positive CML.

Ponatinib in treatment of chronic myeloid leukemia with T315I mutation

Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation t(9;22)(q34;q11) which causes the formation of the Philadelphia chromosome (Ph). Therapeutic progress made in the last two decades and new-generation tyrosine kinase inhibitors (TKIs) introduction, signifi cantly increased patients’ prognosis. We present a case study of a Ph-positive CML patient with a point BCR/ABL1 mutation T315I treated with ponatinib.

Pharmacotherapeutic Options for Philadelphia Chromosome-Positive CML

Chronic myeloid leukemia (CML) is a myeloproliferative disorder of hematopoietic stem cells. Identifying the leading mutation in BCR-ABL that causes CML made it possible to develop a targeted approach against this vastly disseminating disease. The active tyrosine kinase protein of BCR-ABL was effectively blocked with an identified tyrosine kinase inhibitor (TKI), imatinib. Imatinib became the first targeted therapy licensed for patients with chronic-phase CML and its introduction was associated with substantial improvements in response and survival compared with previous therapies. However, drug resistance towards imatinib therapy soon emerged and hence limited the complete eradication of CML in patients receiving imatinib. This is primarily due to the mutations within the ABL kinase domain, and to a lesser degree, due to residual disease after treatment. Nilotinib and dasatinib were soon introduced and showed improved clinical outcomes in patients intolerant and resistant to imatinib treatment. However, the T315I mutant overcame these agents along with imatinib, rendering the treatment ineffective. Exploring the kinase domain of the BCR-ABL protein and identifying key components involved in the signal transduction pathways is crucial towards understanding the disease and developing better strategic approaches towards combating it. In this review, we broadly discuss the current treatment options available against Philadelphia chromosome (Ph) positive BCR-ABL CML.

Philadelphia chromosome positive chronic myeloid leukemia with 5q deletion at diagnosis

BackgroundAlthough, molecular genetic analyses became more and more important to guide therapy decisions in leukemia, banding cytogenetic analysis has retained its vital role in diagnosis and monitoring of chronic myeloid leukemia (CML), by quick and easy enabling identification of pathognomonic Philadelphia chromosome (Ph).Case presentationA 45 year old female presented with characteristic hematological features of CML in chronic phase; cytogenetic studies revealed the presence of the typical Ph and a deletion of almost entire long arm of a chromosome 5.Conclusion5q deletions have rarely been reported in CML. Those seen yet were either associated with tyrosine kinase inhibitor therapy or detected post allogeneic stem cell transplantation. To our knowledge, this is the first case of Ph positive CML accompanied by a 5q deletion.

Ponatinib: A drug review

The discovery of Philadelphia (Ph) chromosome in 1959 was a landmark moment in the history of targeted therapies for cancer. The BCR-ABL fusion gene formed as a result of this translocation is the key pathogenetic event of chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (ALL). Currently, there are five tyrosine kinase inhibitors (TKIs) available in the clinic to target the BCR-ABL kinase. The last one to be added to the list is ponatinib. Ponatinib is highly effective even in the presence of mutations such as T315I that render all other TKIs ineffective. The initial enthusiasm following the impressive results from the Ponatinib Ph-positive ALL and CML Evaluation (PACE) trial was dampened by the emergence of arterial occlusive events. With a dose-adapted strategy, the drug seems to be ready for a comeback. We review the drug ponatinib, including the history, chemistry, mechanism of action, pharmacokinetics, clinical trial data, ongoing clinical trials, and adverse events.

Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a rare hematopoietic stem cell disease that is typically characterized by the abnormal BCR-ABL1 fusion gene on the Philadelphia (Ph) chromosome in neoplastic cells. Dasatinib (Sprycel®) is an orally administered, small molecule tyrosine kinase inhibitor indicated for the treatment of certain hematological malignancies, including Ph-positive CML in the chronic phase (Ph+ CML-CP) in adult and pediatric patients. In open-label phase 1 and phase 2 clinical trials, dasatinib produced early and durable target responses (i.e. molecular, cytogenetic and/or hematologic) in pediatric patients with Ph+ CML-CP that was newly diagnosed or resistant/intolerant to imatinib, with some recipients of the drug also experiencing deep molecular responses. Dasatinib therapy in pediatric patients with Ph+ CML-CP was reported to have a similar safety profile to that observed in adults, except there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, or pulmonary hypertension adverse events. Although long-term outcomes remain to be determined, dasatinib expands the first- and second-line options available for the treatment of Ph+ CML-CP in pediatric patients.

Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches

Chronic myeloid leukemia (CML) is a neoplastic disease whose genetic and cytogenetic changes play important roles in prognosis and treatment strategies. Philadelphia (Ph) translocation t(9;22)(q34;q11) is a diagnostic and prognostic biomarker in CML. Pubmed and Google Scholar databases were searched for English language articles from 1975 to 2017 containing the terms CML; Additional chromosomal abnormalities; Philadelphia translocation; Prognosis; and Treatment. Approximately 10-12% of CML patients exhibit additional chromosomal aberrations (ACAs) in chronic phase and blast crisis. ACAs emergence may cause different features in CML patients according to Ph pattern. For instance, deletion of chromosome 9 derivation is associated to patient's bad survival, whereas monosomy 7 develops myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) in CML patients with Ph-negative pattern. And ACAs in Ph-positive CML is considered as a failure in the management of CML with imatinib. CML classification using different features such as Ph and ACAs can play a decisive role in the evaluation of treatment responses in patients, for example, CML patients with Ph negative and monosomy 7 develop MDS or CML patient -Y and extra copy of Ph have a good response to tyrosine kinase inhibitors, therefore, classifications according to Ph and ACAs play an important role in choosing better treatment protocols and therapeutic strategies. Karyotype analysis in CML patients with complex karyotype shows unrandom pattern so ACAs can be great clue in medical guidelines.

Prognostic Value of Clonal Evolution at the Time of Diagnosis in Patients with Chronic Myeloid Leukemia Treated with Frontline Tyrosine Kinase Inhibitors

Introduction:Additional cytogenetic clonal evolution (CE) is a known risk factor for a poor prognosis in chronic myeloid leukemia (CML). However, its prognostic significance in the setting of new tyrosine kinase inhibitor (TKI) remains unclear. We sought to analyze the baseline characteristics and clinical outcome in chronic phase (CP) CML pts with or without CE treated on frontline TKI clinical trials in a single institution.Methods:Patients (pts) with Ph-positive CML in CP with or without CE at the time of diagnosis receiving initial therapy with imatinib 400 mg/d, imatinib 800 mg/d, dasatinib 100 mg/d, nilotinib 800 mg/d or ponatinib 30 or 45 mg/d in consecutive or parallel clinical trials at a single institution were analyzed. Overall survival (OS), transformation free survival (TFS), event free survival (EFS), failure free survival (FFS) were analyzed from the start of therapy by Kaplan-Meier method. Clonal evolution (CE) was defined by the presence of any cytogenetic abnormality other than a single Ph, variant Ph chromosome or loss of Y chromosome. Also we analyzed CML pts with CE with regard 'major route' abnormalities vs other. The major route abnormalities includes trisomy 8 (+8), trisomy 19 (+19), isochromosome 17q10 (i17q) and additional Ph chromosome.Results:A total of 603 pts were analyzed including 579 pts in CP without CE and 24 pts with CE. Pts in CP without CE received initial therapy with imatinib-400 (n=70), imatinib-800 (n=200), dasatinib (n=138), nilotinib (n=122), or ponatinib (n=49), and pts with CE received imatinib-400 (n=2), imatinib-800 (n=7), dasatinib (n=10), nilotinib (n=4), and ponatinib (n=1). Pts with CP were usually older, female and have a higher WBC (P < 0.001). There was a statistically significant higher Complete cytogenetic response (CCyR) at 6 mo in pts without CE (P = 0.012), however the cumulative and 3-month rates of complete hematologic response (CHR), and the cumulative rates of CCyR and MMR were not different (Table). Similarly, the rates of MR4.0 and MR4.5 were similar for the two groups. At 5 years, the presence of additional cytogenetic findings at diagnosis does not seem to affect the rate of transformation, failure-free, event-free and overall survival. Acknowledging the small sample size for subset analysis, response rates and survival outcomes were comparable in CP with CE irrespective of whether chromosomal abnormalities were ’major route’ or other (n=12 in each arm).Conclusion:Additional cytogenetic CE at the time of diagnosis among patients with CML in CP is associated with a similar favorable outcome as those without CE when treated with TKI. The type of additional CE (major route vs other) does not seem to impact outcome. Patients with CML-CP with CE at the time of diagnosis can thus be treated with TKI as all other pts with CP with no need for consideration for SCT unless there is clear evidence of failure. DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. DiNardo:Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract 2428: Genetic aberrations in the DNA repair pathway among children with Philadelphia chromosome positive leukemias

Abstract Background. Aberrations in the DNA repair pathway among children with leukemia are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. Germline aberrations of the DNA-repair machinery are crucial for generating chromosomal instability and occurrence of acute leukemia in children. In order to better understand this mechanism, we studied a specific subgroup of childhood leukemia, e.g. t(9;22) or chromosome Philadelphia positive (Ph+) acute lymphoblastic and chronic myeloid leukemias. We addressed our research to specific genes (Nijmegen Breakage Syndrome (NBS1) and Fanconi Anemia) involved in the DNA repair pathway, in the attempt to identify mutations and aberrant expressions, predisposing and/or cooperating with the leukemogenic process. Materials and Methods. We analyzed diagnostic and remission samples of 12 children: 8 with a Ph+ acute lymphoblastic leukemia (ALL) and 4 with a chronic myeloid leukemia (CML) diagnosed and treated at our institution from 1999 to 2013. We performed RT-PCR analyses to detect mutations in exons 3-6 of the NBS1 gene, followed by a direct sequencing analysis (BMR - Padova - Italy). The status of FANCD2 and PALB2 genes was studied by a multiplex ligation-dependent probe amplification (MLPA) using the Salsa MLPA P057-025R FANCD2-PALB2 Probemix and SALSA MLPA EK1 kit (MRC-Holland, Amsterdam, the Netherlands). Samples from five healthy donors (HDs) were used as wild-type controls. For data elaboration, we used Coffalyser.Net software for MLPA. Moreover we performed a real-time PCR amplification of BRCA1 (exons 14-15) and BRCA2 (exons 15-16) genes, respectively, calculating the median fold-changes (MFC) in patients comparing with HDs. Results. We detected the NBS1 E185Q polymorphism (c533G&amp;gt;C, rs1805794) in both diagnostic and remission samples in 3 out of 12 children with a Ph positive acute leukemia (2 ALL, 1 CML). We also found two pairs of deletions in FANCD2 (Δ32-35; Δ35-38) and PALB2 (Δ2; Δ2-6) in 4 out of 12 Ph positive cases (2 ALL and 2 CML). These aberrations were mutually exclusive. Thus a total of 7 cases (58%) showed an aberrant pathway. Moreover we determined that the MFC of BRCA1 expression among children with Ph positive ALL and CML was slightly higher than HDs (1,388 vs 0,433 and 1,625 vs 0,451, respectively). Surprisingly the MFC of BRCA2 expression was strongly higher than HDs in both children with Ph positive ALL (5,924 vs 0,002) and CML (54,504 vs 0,256). Conclusion. Our preliminary findings strongly suggest that germline mutations or deletions in association with aberrant expression of specific genes that regulate the DNA repair machinery may contribute to the chromosomal instability in children with Ph positive leukemias. These data will be confirmed in a larger population of different subtypes of pediatric leukemia. Citation Format: Nellina Andriano, Paola Bonaccorso, Valeria Iachelli, Manuela La Rosa, Emanuela Cannata, Luca Lo Nigro. Genetic aberrations in the DNA repair pathway among children with Philadelphia chromosome positive leukemias. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2428.

Cutaneous Lesions Anticipating Accelerated Phase of Multidrug Resistant Chronic Myeloid Leukemia Responsive to Ponatinib.

Ponatinib a third generation tyrosine kinase inhibitor, has been approved for all phases of disease in CML. In advanced phase, has been confirmed with a good efficacy in all type of resistance, including T315I kinase domain mutation. We here report activity of the drug in advanced phase with extramedullary localization.

Survivin and SIRT1: can be two prognostic factors in chronic myeloid leukemia?

Antiapoptotic molecules are important in the development, progression, and prognosis of malignant disorders. The aim of this study was to determine the expression of two distinct antiapoptotic molecules, SIRT1 and Survivin (SVV), in chronic myeloid leukemia (CML) and to compare them with hematological prognostic factors. In this study, we measured the expression of SVV and SIRT1 in 18 patients with typical Ph-positive chronic myeloid leukemia in chronic phases of the disease as well as in 18 matched healthy donors. SVV, SIRT1, and BCR/ABL expression were determined by quantitative-real-time polymerase chain reaction (Q-RT-PCR). HPRT was used as a reference gene to calculate SVV/HPRT and SIRT1/HPRT ratio, and ABL was used as an internal control for BCR/ABL expression. SVV was between 0.00 and 2.39-fold (median 0.204) and SIRT1 was between 0.00 and 33.32-fold (median 0.186). In our study, both SVV and SIRT1 were lower in patients than in the controls (p = 0.001 and 0.001, respectively). Although the expression of SVV and SIRT1 was decreased in patients with chronic phase (0.043 and 0.043-fold, respectively), a potent expression upregulation of both genes was found in K562, Jurkat, and U937 cell lines. Despite lower expression of both SVV and SIRT1 at chronic phase, a significant correlation was found between SVV expression levels and minor Hb concentration (<10) (p = 0.005). In addition, there was important correlation between BCR/ABL copy number and older age (≥60) and PLT count (p = 0.027 and p = 0.001, respectively). Of course, no specific clinicohematological or prognostic profile was associated with SIRT1 expression. In contrast with SIRT1 expression, high SVV expression and high BCR/ABL copy number could be introduced as prognostic factors in chronic phase of CML, but this finding must be evaluated in other phase of CML and with a higher number of subjects.

Bosutinib for the treatment of chronic myeloid leukemia.

The pharmacology, pharmacokinetics, efficacy, and safety of the tyrosine kinase inhibitor (TKI) bosutinib in the management of chronic myeloid leukemia (CML) are reviewed. Although clinical outcomes are favorable in patients wth Philadelphia chromosome (Ph)-positive CML who receive first-line TKI therapy with imatinib, dasatinib, and nilotinib, disease progression or relapse may occur. Thus, effective second-line agents are crucial. Bosutinib (Bosulif, Pfizer Inc.) is a second-generation TKI approved for the treatment of patients with Ph-positive chronic-, accelerated-, or blast-phase CML who are intolerant or resistant to other TKIs. Bosutinib inhibits a tyrosine kinase oncogene and Src kinases responsible for CML pathogenesis. Bosutinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4; therefore, concomitant use of strong or moderate CYP3A4 inhibitors and inducers should be avoided. Bosutinib is effective in cases involving most imatinib-resistant mutations (not including the T315I and V299L mutations). Clinical trials demonstrated bosutinib's efficacy in inducing durable hematologic and cytogenetic responses, as well as high rates of progression-free and overall survival, in patients with CML who had developed resistance or intolerance to other TKIs. However, bosutinib was not found to be superior to imatinib for inducing cytogenetic responses in cases of newly diagnosed CML and is thus not indicated for use in TKI-naive patients. The most common adverse events among bosutinib-treated patients in clinical trials were diarrhea, nausea, and vomiting, which were generally transient and self-limited. Bosutinib is a safe and effective second-line treatment option for select patients with Ph-positive CML who were intolerant or resistant to prior TKI therapy.

Spectrum of BCR-ABL Kinase Domain Mutations; A Cohort Study from Saudi Arabia

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) associated with a characteristic translocation between chromosome 9 and 22 to form Philadelphia chromosome (Ph). The introduction of tyrosine kinase inhibitors (TKIs) imatinib for CML marked a new era for targeted therapy. In general CML patients in chronic phase (CP) have a very good response to Imatinib with a ~85% projected overall rate of survival. However, a significant proportion harbor molecular residual disease and develop acquired resistance after initial response through a number of cellular and molecular mechanisms in which mutations in the Abl kinase domain are the best known cause of resistance. Mutations are detected in 35% of patients with resistance to TKI in Chronic Phase and up to 80% in patients with accelerated phase and blast phase.Given the clinical importance of the mutation status, mutation analysis was established as a clinical service to aid in the clinical decision and identify the subset who would benefit from alternative therapies.In this retrospective study, we assessed the ABL kinase domain mutation in 93 patients referred from our clinics at King Faisal Specialist Hospital and Research centre (General Organization) between 2011-2013 with Ph positive CML displaying either refractory to TKI or resistance displaying increase BCR-ABL1 levels by serial monitoring using Quantitative PCR. Mutation analysis was performed on RNA extracted from either blood or Bone marrows after amplification of the BCR/ABL1 transcript by nested PCR followed by Direct sequencing of the BCR-ABL1 Kinase domain including residues 243-487.In total, 93 patients (46 Females and 47 males), Age between 10-71 years (median age: 38 years) of which 89 were adults and 4 pediatrics were analyzed. Among 93 patients, 20 (21.5%) were positive for 10 different mutations across the ABL1 Kinase domain mutations (7 patients had T315I, 3 patients had each of the following mutation: Y253H, F359I, 2 patients with E255K. Additionally, one patient with each of the following mutations: E355G, V299L, L248V, L298, Y326H and F317L). The duration from diagnosis to mutation detection ranged between 3-144 months with a median duration of 4 years.Despite the retrospective nature and the relatively small sample size of a single center analysis, the mutation frequency is in line with similar studies reported from our region.Further follow up is needed to identify the outcome of these patients acquiring ABL kinase mutations on targeted therapy. DisclosuresNo relevant conflicts of interest to declare.

Strategic therapeutic approaches to overcome emerging dual SRC/ABL kinase inhibitors resistances in chronic phase Ph positive chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a haematopoietic neoplasm with clinically distinct phases and BCR⁄ABL1 oncogene. Imatinib mesylate, a potent inhibitor of BCR-ABL was highly effective in CML but later in-vitro derived cell line with resistance namely BCR-ABL duplication point mutation, P loop mutation, T315I mutation, C helix, SH2 domain, activation loop, C terminal lobe, SRC family kinase activation led to development of Nilotinib. Although it has potential drug targets as BCR-ABL kinase, KIT, PDGFR but has no role in overcoming in Src family kinase. It prompted strategic rational drug design of Dual Src Family Kinase/Abl Inhibitor Dasatinib, active against 15 clinically significant Imatinib resistant BCR-ABL mutations but inactive against T315I mutation. The propensity of Ph+ CML to develop novel mechanism of resistance led designing of rational therapeutic approaches to eradicate minutest residual diseases along with long term resistance risk. DOI: http://dx.doi.org/10.3126/ajms.v6i1.10454 Asian Journal of Medical Sciences Vol.6(1) 2015 8-15

Trisomy 19 as the Sole Chromosomal Abnormality in CML

Presence of trisomy 19 in chronic myeloid leukemia (CML) normally considered as secondary abnormality but trisomy 19 rarely occur as sole abnormality. In the present study a total of 2312 Ph positive CML were screened from year2004 to 2014 and we found 2 cases of trisomy 19 as sole karyotype abnormalities. Both karyotype showed 47,XY,t(9;22)(q34;q11.2),+19,complements. It is not known that which gene(s) present on chromosome 19 plays important role in development of this condition.

Prognostic importance of additional cytogenetic anomalies in chronic myeloid leukemia

Additional chromosomal abnormalities (ACAs) in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) are strongly associated with disease progression, but their prognostic impact and effect on treatment response are not clear. While the onset of ACAs in Ph-negative cells during treatment has been described, their origin and clinical significance remain to be clarified. Between January 2008 and January 2011, 105 patients with Ph-positive CML were analyzed. With a median follow-up of 25.5 months, 18 CML patients (17 %) with ACAs in either CP (n = 12) or advanced phases (n = 6) were identified. The median age of the patients was 53.5 years at diagnosis. ACAs were determined in Ph-positive metaphases of 12 patients and in Ph-negative metaphases of 5 patients. One patient showed trisomy 8 both in Ph-positive and in Ph-negative metaphases. The median follow-up after the detection of ACAs was 11.9 months. None of the patients carrying ACAs in their Ph-negative metaphases developed AP or BP; however, 7 out of 12 patients (58 %) having ACAs in their Ph-positive metaphases developed AP/BC at diagnosis or follow-up (p = 0.03). All the patients carrying ACAs in only Ph-negative metaphases achieved optimal response under tyrosine kinase inhibitor (TKI) therapy, whereas only 4 out of 12 patients (25 %) had optimal TKI response in patients with ACAs in Ph-positive metaphases (p = 0.009). The presence of ACAs in Ph-positive cells during TKI therapy may reflect genetic instability and therefore negatively affect OS. Conventional cytogenic analyses remain mandatory during follow-up of patients with CML under TKI therapy.