Argentine Registry of Hematologic Disease (RAEH) Chronics Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4455-4455
Author(s):  
Alicia Inés Enrico ◽  
Beatriz Moiraghi ◽  
Graciela Klein ◽  
Maria del Rosario Cabrejo ◽  
Renee Crisp ◽  
...  
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Target Population ◽  
First Year ◽  
Disease Epidemiology ◽  
Environmental Causes

Abstract Abstract 4455 Introduction: The CML Registry was developed by the Argentine Society of Hematology as a part of the centralized RAEH. Results from epidemiologic and clinical data related to CML, will enable to determine the geographic distribution of the target population, to establish associated environmental causes, and mainly to rationalize resources supply. Objective: a) To analyze characteristics of CML patients registered in the RAEH; b) To evaluate the CML Registry performance through its first year. Materials and Methods: Patients with CML registered in the RAEH from January 1st, 2011 up to July 31st, 2011. The protocol allowed to enroll de novo patients as well as patients diagnosed from 2000 on. Result: Data reported by 15 hospitals were included: 224 patients were registered. Mean age was 50 (18–86 y) and gender distribution was female: 102, male: 122. Occupational data showed no a characteristic pattern. 96.5% of patients were diagnosed in chronic phase, while 3.5% were diagnosed in accelerated phase/blast crisis. In 6% of patients cytogenetic tests detected 8 abnormalities besides t(9,22): double Philadelphia chromosome and monosomy 12 were the most frequent findings. FISH tests were recorded for 18% of patients at the time of diagnosis. Bone marrow biopsy was reported as a diagnostic procedure in 51%. Qualitative BCR/ABL was recorded for 31% of patients at the time of diagnosis. Molecular RQ-PCR tests for follow-up of treatment response were reported for 51% of patients. Of the registered population, 21% received interferon as previous therapy to Imatinib (IM); 89% received IM 400mg daily; 6% required dose increase. Second line treatment with dasatinib or nilotinib was recorded in 34% and 14% of patients, respectively. At 60 months mean follow-up 8% of the registered population had developed blast crisis and 6% had died. Conclusions. The RAEH’s first year of performance in CML was assessed. This only reflects the experience with 15 sites. Data registered will allow us in the following years to learn about disease epidemiology and available resources to improve patient accessibility. Disclosures: No relevant conflicts of interest to declare.

Imatinib (IM) Treatment In Chronic Myeloid Leukemia (CML). Clinical Practice Limitations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4454-4454
Author(s):  
Alicia Inés Enrico ◽  
Georgina Bendek ◽  
Maria Virginia Prates ◽  
Virginia Guerrero ◽  
Juan Jose Napal ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Trisomy 8 ◽  
History Of ◽  
One Year

Abstract Abstract 4454 Introduction: CML represents 15% all of oncohematologic diseases in adults. IM changed the history of the disease. At one year of treatment, the emblematic IRIS study showed Major Cytogenetic Responses (MCyR) of approximately 87% and Complete Cytogenetic Responses (CCyR) of around 76%, with PFS to accelerated phase or blast crisis of 97.7% and 91.5%, respectively. Objective: To assess treatment characteristics and responses in a group of patients treated with IM in clinical practice. Materials and Method: 113 medical records of patients with CML diagnosed between 1998–2011 from two institutions in the Argentine Republic were retrospectively analyzed. Result: Mean population age was 46 years old (r 18–73) 65 male, 48 female. 97% in chronic phase, the rest in accelerated phase. 31% presented comorbidities at diagnosis. Cytogenetic abnormalities at diagnosis, in addition to the classic t(9:22), included: trisomy 8 and double Philadelphia chromosome in 4 tests. Only 7 patients had qualitative BCR/ABL determined at diagnosis. 25% had received interferon, patients received IM 400 mg and only 2% received 300 or 600 mg doses. 2.6% of patients did not achieve CHR. Cytogenetic responses assessed at any time of treatment were: Major: 12%, Minor 20%, Complete 51%, None 3%, 14% were not assessed. With a mean follow-up time of 46 months, the overall survival was 75%. 10% of patients progressed to BC/AP, 11 % of patients died due to disease-related causes or comorbidities. Conclusions: With a mean follow-up time of 46 months for chronic phase CML, treatment with IM achieved complete cytogenetic responses in 51% of patients, and progression occurred in 10% of patients. Disclosures: No relevant conflicts of interest to declare.

Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4499-4499
Author(s):  
Santiago del Castillo ◽  
Regina Garcia Delgado ◽  
Laura Entrena ◽  
Agustin M Hernandez ◽  
Arturo Campos ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Genetic Material ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Current State ◽  
Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

ACase Of Asymptomatic Pediatric Chronic MyelogenousLeukemia With Hyperleukocytosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5198-5198
Author(s):  
David A Berger ◽  
Ishmael Jaiyesimi ◽  
Paras Khandhar
Keyword(s):  
Blood Cell ◽  
White Blood Cell ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Pediatric Intensive Care ◽  
Direct Result ◽  
Costal Margin ◽  
Outpatient Basis

Abstract Introduction Chronic Myeloid Leukemia (CML) represents 3% of pediatric leukemias. The natural history and molecular biology of pediatric CML is the same as those of older patients with CML. 95% of pediatric CML presents in asymptomatic chronic phase and the rest diagnosed in accelerated or in blast crisis stage. It is reported that patients with pediatric CML have higher white blood cell (WBC) counts and thereby have higher incidence of symptomatic leukostasis compared to adults. Sparse literature exists on particular triggers for treatment with leukapheresis (LA). We present a case of asymptomatic hyperleukocytosis (HL) secondary to pediatric CML and a brief discussion of treatment in this emergency. Objective To report a rare case of asymptomatic pediatric CML with HL. Case Summary A 9-year-old Caucasian male presented to his pediatrician on the outpatient basis for well child care and was found to have a WBC of > 200,000 and then was admitted to the Pediatric Intensive Care Unit for further management. Upon arrival in the PICU, pt was found to have splenomegaly (down 4-5 cm from the costal margin) and hepatomegaly (2 cm down from costal margin). CBC revealed hemoglobin of 7.4 g/dL, platelet of 883 bil/L and a total white blood cell count (WBC) of 302.7 bil/L. A differential on the WBC revealed 43.9 basophils, 24.2 blasts, and 6.1 promyelocytes. Flow cytometry showed prominent myeloid population with 5% CD34 positive myeloblasts and a prominent basophil population, consistent with morphological expression of CML. The cytogenetic analysis revealed a t(9,22)(q34;q11) translocation consistent with a Philadelphia chromosome. Pediatric Leukaphresis (LA) for cytoreduction was not available at our facility, thus he was transferred. Discussion The HL in this patient is a direct result of his pediatric CML. The decision regarding need for cytoreduction with LA has been described in the literature for symptomatic children, but no case has been reported of when to perform LA when no symptoms of leukostasis are present. Conclusions In this case, it was discovered that the trigger(s) to perform LA is vague in the literature, as well as controversial in practice especially with well appearing children with the potential for a swift precarious demise. Further studies and meta-analyses to uncover the proper triggers for LA are warranted. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Detection of Compound BCR-ABL Mutations in TKI Resistant CML Patients Including a Novel K245N Mutation Associated with Primary Nilotinib Resistance By Employing a Newly Developed Cost Effective BCR-ABL Sequencing Protocol

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1810-1810
Author(s):  
Zafar Iqbal ◽  
Tanveer Akhtar ◽  
Afia M Akram ◽  
Muhammad Khalid ◽  
Ijaz Husssain Shah ◽  
...  
Keyword(s):  
Third World ◽  
Mutation Detection ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cost Effective ◽  
Optimization Techniques ◽  
Mutation Status ◽  
Imatinib Resistant

Abstract Introduction: BCR-ABL mutations are the major background players in manifestation of resistance to all FDA approved tyrosine kinase inhibitors (TKIs) including imatinib, dasatinib, nilotinib, Bosutinib and ponatinib 1. Detection of mutations is a vital part of European or North American clinical guidelines at the time of resistance and/or drug switching, because resistance-causing mutations appearing as a result of one drug are sensitive to other in many instances and mutational data can therefore help in prescription of better alternative TKI in case of resistance or unsatisfactory response 1,2. Although BCR-ABL sequencing protocols are reported, they either lack the experimental details or are not cost-effective to be used in third world countries 1’3. Therefore, objective of this study was to develop a cost-effective protocol for BCR-ABL mutation detection in TKI resistant CML. Material and Methods: Peripheral blood samples were collected from 10 imatinib resistant, 10 imatinib sensitive, 5 CML patients receiving nilotinib, positive for Philadelphia chromosome by conventional cytogenetics, and 10 healthy volunteers. Isolation of RNA was performed using TriZol® LS reagent and complementary DNA (cDNA) was prepared using random hexamer primers. The integrity of cDNA was checked by amplification of housekeeping gene GAPDH. A nested RT-PCR assay was optimized for ABL kinase domain amplification using standard PCR optimization techniques. PCR bands of 1306 or 1380 base pairs, corresponding to b2a2 and b3a2 BCR-ABL splice variants, were detected in 25 CML patients but no healthy controls. Consumables for CDNA and PCR were used from Fermentas (USA). PCR products were purified using Quick gel extraction kit (Invitrogen). DNA sequencing was performed using BigDye® Terminator v3.1Cycle Sequencing Kit (Applied Biosystems). Results: Compound mutations were detected in CML patient showing primary resistance to nilotinib, including a novel K245N mutation and G250W mutations (Figure 1) while 4 of nilotinib responders did not show any mutations. Similarly, mutations detected in four (4/10, 40%) imatinib resistant were (G250W), (T394A), (Y253H), (E355G, Y393H}. Of 10 imatinib sensitive patients, mutations were detected in 3, 2 in accelerated phase and 1 in blast crisis, while none in 7 c chronic phase CML (Figure 2). Discussion: We show association of BCR-ABL mutations with imatinib/nilotinib resistance and disease progression in CML patients, which is in accordance with previous studies 1’2’4,5. This also proves the usefulness and applicability of our BCR-ABL sequencing protocol for detection of clinically relevant mutations in CML patients receiving TKI treatment. A cost effective protocol it will facilitate the incorporation of mutation detection in clinical setting in low-resourced laboratories from third world countries and thus help better manage clinical interventions in drug-resistant CML 6’7. References: 1. Baccarani M, Soverini S, De Benedittis C. Am Soc Clin Oncol Educ Book. 2014:167-75. 2. Kang Y, Hodges A, Ong E, Roberts W, Piermarocchi C, Paternostro G.PLoS One. 2014 Jul 16;9(7):e102221. 3. Branford S, Hughes T. Methods Mol Med. 2006; 125:93-106. 4. Viganò I, Di Giacomo N, Bozzani S, Antolini L, Piazza R, Gambacorti Passerini C. Am J Hematol. 2014 Jul 15. 5. Balabanov S, Braig M, Brümmendorf TH. Drug Discov Today Technol. 2014 Mar;11:89-99. 6. Jabbour E, Kantarjian H. Am J Hematol. 2014 May;89(5):547-56. 7. Kagita S, Jiwtani S, Uppalapati S, Linga VG, Gundeti S, Digumarti R. Tumour Biol. 2014 May;35(5):4443-6. Figure 1: Electropherogram showing compound mutations, including a novel BCR-ABL mutation associated with primary nilotinib resistance in CML patient Figure 1:. Electropherogram showing compound mutations, including a novel BCR-ABL mutation associated with primary nilotinib resistance in CML patient Figure 2: Response to imatinib and BCR-ABL mutation status in CML patients Figure 2:. Response to imatinib and BCR-ABL mutation status in CML patients Disclosures No relevant conflicts of interest to declare.

Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7052-7052 ◽  
Author(s):  
Richard A. Larson ◽  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Saengsuree Jootar ◽  
...  
Keyword(s):  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Risk Of Progression ◽  
Peripheral Arterial ◽  
To Receive

7052^ Background: In the 3-y follow-up (f/u) of ENESTnd, NIL demonstrated superior rates of molecular response and reduced progression to accelerated phase/blast crisis (AP/BC) vs IM. Here, we report results with a minimum f/u of 4 y. Methods: 846 adults with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Results: NIL continued to demonstrate higher rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS), MR4 (≤ 0.01%IS), and MR4.5 (≤ 0.0032%IS) vs IM (Table). No new progressions have occurred on treatment on any arm since the 2-y analysis. NIL had significantly lower rates of progression to AP/BC on treatment (n = 2, 3, and 12 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and when including f/u after discontinuation (n = 9, 6, and 19 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and higher overall survival (OS) vs IM. By 4 y, half as many pts acquired new BCR-ABL mutations on study with NIL vs IM (n = 12, 11, and 22 on NIL 300 mg BID, 400 mg BID, and IM, respectively). Since the 3-y analysis, 2 new mutations (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM) were reported. Safety profiles of both drugs were consistent with previous ENESTnd analyses. By 4 y, peripheral arterial occlusive disease (PAOD) events were reported in 4 and 5 pts in the NIL 300 mg BID, and 400 mg BID arms, respectively. No pt in the IM arm had a PAOD event. Conclusions: ENESTnd 4-y data continue to demonstrate the superiority of NIL over IM for achieving deeper responses with lower risk of progression, supporting the use of NIL as frontline therapy in CML-CP. Clinical trial information: NCT00471497. [Table: see text]

scholarly journals Treatment of chronic myeloid leukemia with Generic Imatinib in patients from Northeastern part of India

2019 ◽  
Vol 10 (4) ◽  
pp. 3107-3113 ◽  
Author(s):  
Siddharth Samrat ◽  
Lalit Prashant Meena ◽  
Jaya Chakravarty ◽  
Madhukar Rai
Keyword(s):  
Side Effect ◽  
Therapeutic Response ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
One Year

Imatinib is now used as the first-line drug to treat CML patient. However, the emergence of resistance to Imatinib in CML patient, the side effect of bone marrow suppression, fluid overload and gastritis are a major limitation of the use of Imatinib in the treatment of CML. This study was conducted to see the therapeutic response and side effect profile of generic Imatinib Mesylate in newly diagnosed CML patients. All cases of CML were given generic Imatinib and followed prospectively with a minimum follow-up of 6 months. They were followed at an interval of 2 weeks till complete hematologic response, thereafter at an interval of 6 to 8 weeks. Cytogenetic and molecular response at the end of one year also evaluated. Among 36 CML patients, 33 were in chronic phase 2 in accelerated phase and 1 in blast crisis while 35 were Philadelphia+ve and 1 was ph–ve at initial presentation. Minimum duration to achieve CHR was 2 week with a mean of 5 weeks. At 3 month except one 35 patients achieved CHR (97%). Out of 36 patients, 27 were subjected for Philadelphia chromosome at one year which shown 23 patients (85.18%) achieved a major cytogenetic response. 8 (38%) patients achieved a major molecular response and one patient (4.76%) was having a complete molecular response at one year. 8 (22.22%) patients developed hematological toxicity to Imatinib with Pancytopenia most common. In conclusion, Generic Imatinib is having an excellent therapeutic response in CML patients although higher response rate may be due to smaller sample size and lesser duration of follow up.

scholarly journals The ''Gatekeeper'' Mutation T315I in BCR/ABL Confers Additional Oncogenic Activities to Philadelphia Chromosome Positive Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5196-5196
Author(s):  
Usva Zafar ◽  
Mohammed Yusuf ◽  
Rikhia Chakraborty ◽  
El-Nasir M A Lalani ◽  
Afsar Ali Mian
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Resistance Mutation ◽  
Chronic Phase ◽  
Syngeneic Mouse Model ◽  
Transformation Potential

Chronic myeloid leukemia (CML) and 30% of adult acute lymphatic leukemia (ALL) are characterized by the Philadelphia chromosome (Ph+), having a (9;22) chromosomal translocation. The BCR/ABL fusion protein is the hallmark of Ph+ leukemia. BCR/ABL is characterized by deregulated and constitutively activated ABL tyrosine kinase activity that determines its transformation potential. Tyrosine kinase inhibitors (TKI) have greatly improved the overall prognosis of these diseases, particularly by altering the natural history of chronic phase (CP) CML and preventing the previously inexorable progression to terminal blast crisis (BC). However, unsatisfactory responses in advanced disease stages, resistance and long-term tolerability of BCR/ABL inhibitors represent major clinical problems. The most important mechanism of resistance against TKIs is the selection of leukemic clones driven by BCR/ABL harboring point mutations, such as the E255K, Y253F/H (P-loop), H396R (activation loop) or the T315I (gatekeeper). The "gatekeeper" mutation T315I confers resistance against all approved TKIs, with the only exception of Ponatinib, a multi-target kinase inhibitor. CML and Ph+ ALL, rarely present at diagnosis with a BCR/ABL harboring a resistance mutation to TKI. Resistant clones may be present and only detectable by highly sensitive methods. We have previously shown that the resistance mutations may influence the biology of BCR/ABL and its transformation potential. We therefore hypothesized that the presence of mutations such as the T315I select for a "dormant cell population" which manifests following initial treatments with TKI inhibitors and treatment failure. The aim of this study was to determine whether the ''gatekeeper'' mutation T315I is able to confer biological features to BCR/ABL influencing its leukemogenic potential. We investigated the influence of T315I on the biology of BCR/ABL in CML and Ph+ ALL. We used Ph+ ALL patient derived long term culture (PDLTCs), factor dependent Ba/F3 cells and syngeneic mouse model of BCR/ABL induced CML-like disease. These models allowed the direct comparison of BCR/ABL with BCR/ABL-T315I. We observed significantly slower proliferation of Ba/F3 cells and PDLTCs expressing BCR/ABL-T315I compared to the native BCR/ABL. This was further confirmed by undertaking mitotic index calculations and colony formation assays on both cell types. Furthermore, the induction of a CML-like disease in syngeneic mice was significantly delayed in the presence of T315I (median: BCR/ABL - 27 days; BCR/ABL-T315I - 61 days). We undertook functional studies to determine the putative signaling pathway and found that Ras/Erk1/2 pathway was activated inT315I positive cells. This study may assist towards therapy decisions in patients with CML/Ph+ ALL with a T315I mutation. Disclosures No relevant conflicts of interest to declare.

RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3735-3741 ◽  
Author(s):  
Catherine Roche-Lestienne ◽  
Lauréline Deluche ◽  
Sélim Corm ◽  
Isabelle Tigaud ◽  
Sami Joha ◽  
...  
Keyword(s):  
Dna Binding ◽  
High Frequency ◽  
Trisomy 21 ◽  
De Novo ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Chromosome 21 ◽  
Imatinib Resistance ◽  
Molecular Abnormalities

Abstract Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.

scholarly journals The Importance of Identification of M-BCRABL Oncogene and JAK2V617F Mutation in Myeloproliferative Neoplasms

2014 ◽  
Vol 60 (2) ◽  
pp. 44-48
Author(s):  
Annamária Szántó ◽  
Zsuzsanna Pap ◽  
Z Pávai ◽  
I Benedek ◽  
Judit Beáta Köpeczi ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Molecular Biology ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Gene Mutations ◽  
Chronic Phase ◽  
Final Diagnosis ◽  
Jak2v617f Mutation ◽  
Myeloproliferative Disease

Abstract Background: The elucidation of the genetic background of the myeloproliferative neoplasms completely changed the management of these disorders: the presence of the Philadelphia chromosome and/or the BCR-ABL oncogene is pathognomonic for chronic myeloid leukemia and identification of JAK2 gene mutations are useful in polycytemia vera (PV), essential thrombocytemia (ET) and myelofibrosis (PMF). The aim of this study was to investigate the role of molecular biology tests in the management of myeloproliferative neoplasms. Materials and methods: We tested the blood samples of 117 patients between April 2008 and February 2013 at the Molecular Biology of UMF Târgu Mureș using RQ-PCR (for M-BCR-ABL oncogene) and/or allele-specific PCR (for JAK2V617F mutation). Results: Thirty-two patients presented the M-BCR-ABL oncogene, 16 of them were regularly tested as a follow-up of the administered therapy: the majority of chronic phase patients presented decreasing or stable values, while in case of accelerated phase and blast phase the M-BCR-ABL values increased or remained at the same level. Twenty patients were identified with the JAK2V617F mutation: 8 patients with PV, 4 with ET, 3 with PMF, 4 with unclassifiable chronic myeloproliferative disease and 1 patient with chronic myelomonocytic leukemia. There was no case of concomitant occurance of both molecular markers. Conclusions: Molecular biology testing plays an important role in the management of myeloproliferative neoplasms: identification of the molecular markers confirms the final diagnosis, excluding secondary causes of abnormal blood count parameters. Regular monitoring of MBCR- ABL expression level is useful in the follow-up of therapeutic efficiency.

scholarly journals Sequence of Second Generation Tyrosine Kinase Inhibitors (TKIs) in the Treatment of Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukaemia - Real World Experience in the UK

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3434-3434
Author(s):  
Jenny Byrne ◽  
Joanne Ewing ◽  
Adam J. Mead ◽  
Heather Oakervee ◽  
Gavin Campbell ◽  
...  
Keyword(s):  
Real World ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Educational Support ◽  
Third Line ◽  
The Uk ◽  
Observation Period

Background: The prognosis of patients with chronic-phase myeloid leukaemia (CML) has drastically improved with the introduction of tyrosine kinase inhibitors (TKIs). During the period of this study, availability of treatment options in the UK were limited and determined by the date reimbursement was granted and when restrictions on the use of individual licensed TKIs were removed. Currently, imatinib, nilotinib and dasatinib are reimbursed for 1st line treatment (1L) with bosutinib and ponatinib reimbursed for 2nd line or subsequent lines of treatment. Aims: The primary aim was to determine the sequence of 2nd generation (2G) TKIs (nilotinib, dasatinib, bosutinib) in patients with chronic-phase Philadelphia chromosome-positive (Ph+) CML who had received their 3rd and subsequent lines of TKIs in a real world UK setting. Methods: A multi-centre, retrospective, chart review was undertaken in the UK from November 2018 to July 2019. To be included, patients had to be aged ≥18 with chronic phase Ph+ CML who had started a third line of TKI treatment between June 2013 and February 2018. Patients were excluded if they had >3-month gap in treatment before progression or relapse, or were treated with a 2G TKI within an interventional clinical study during third line treatment. At each line, molecular responses, cytogenetic responses, duration of therapy and reasons for stopping were recorded until the date of last hospital follow-up or death. Overall survival was determined from date of initiation of 3rd or 4th line TKI therapy until death by any cause. Results: An interim analysis was undertaken for 65 patients from 11 sites. Median age at diagnosis was 53.0 years. 50.8% were male and 49.2% were female. Of these 65 patients, 48 patients were still being treated at the end of observation (29 patients in 3rd, 18 in 4th and 1 in 5th line). Patient demographics are typical of CML populations. Throughout the study, imatinib was 1L treatment of choice for the majority of patients (57/65; 88%) and this held true (21/22; 95%) even when nilotinib and dasatinib were reimbursed for use 1L. Nilotinib was most commonly prescribed in 2L (42/65; 56%), reflecting the greater availability of this drug during the study period. Dasatinib and bosutinib constituted 22% and 4% respectively of 2L treatments. The most frequent sequencing pathway observed was I1-N2-D3 (Table 1, Fig. 1). 19 other pathways at low frequencies were observed across 39 patients. 97% of patients (63/65) achieved an optimal response at any time as defined by the 2013 ELN guidelines (Table 2) during the observation period. Of the 31 (48%) patients who were resistant to 1L, 24 (37%) achieved a response in 2L and of the 7 (10.7%) patients who were resistant to 1L and 2L, 5 (7.7%) achieved a response in 3L. At the end of the observation period, only 2 (3%) patients never achieved a response. In 3L: 29 (45%) patients are still ongoing, 4 died, 3 were lost to follow up and 3 underwent transplantation. In 4L: 18 (69%) are still ongoing, 3 died, and 3 underwent transplantation. Median overall survival for L3 was 21 months and 12 months in L4. In all lines of treatment, the main cause of switching away from imatinib was lack of efficacy (61%), and for all 2G TKIs the main cause was intolerance (66%). During the period when only imatinib was available in 1L, median duration of 1L treatment was longer at 26 months for patients failing to respond vs 9 months when nilotinib and dasatinib were also available. Conclusions: In this UK real-world study, for patients requiring 3 or more lines of treatment, sequencing of TKIs may have been determined by drug reimbursement. As availability of TKIs increased, time to switch therapy decreased for all patients, suggesting that clinicians were following guidelines and switching treatments more readily. However, initial 1L prescribing behaviour has not changed in this observation period despite better access to 2G TKI, and there appears to be a trend of physicians preferring to repeat 2G TKIs treatment sequences that yield a favourable outcome. Disclosures Byrne: Ariad/Incyte: Honoraria, Speakers Bureau. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . Mead:Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; CTI: Honoraria, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding. Oakervee:Novartis: Honoraria; Pfizer: Honoraria; Bristol Myers-Squibb: Honoraria. Campbell:Novartis: Consultancy, Other: Educational support; Takeda: Consultancy, Other: Educational support; Bristol Myers-Squibb: Other: Educational support; Roche: Other: Educational support; Celgene: Other: Educational support. Amott:Celgene: Other: Meeting attendance sponsorship . Goringe:Novartis: Consultancy, Other: Speaker. Heartin:Celgene: Other: Speaker's fees; Janssen: Other: Speaker's fees; Takeda: Other: Speaker's fees; Alexion: Other: Speaker's fees; Novartis: Other: Speaker's fees. Dimitriadou:Celgene: Other: Meeting attendance sponsorship . Arami:Takeda: Other: Meeting attendance sponsorship ; Gilead: Other: Meeting attendance sponsorship ; Roche: Other: Meeting attendance sponsorship ; Celgene: Other: Meeting attendance sponsorship . Neelakantan:Novartis: Honoraria; Celgene: Honoraria. Frewin:Novartis: Consultancy, Other: Meeting attendance sponsorship ; AbbVie: Other: Meeting attendance sponsorship . Pillai:Celgene: Honoraria. De Lavallade:BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte biosciences: Honoraria, Research Funding, Speakers Bureau. Cross:Novartis: Consultancy, Research Funding; Incyte: Consultancy. Thompson:Incyte: Employment.

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