scholarly journals A Case Report of BCR-ABL-JAK2-Positive Chronic Myeloid Leukemia with Complete Hematological and Major Molecular Response to Dasatinib

2021 ◽  
Vol 14 (1) ◽  
pp. 690-694
Author(s):  
Elrazi Awadelkarim Hamid Ali ◽  
Susanna Al-Akiki ◽  
Mohamed A. Yassin
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Chromosomal Translocation ◽  
Cytogenetic Response ◽  
Response To Treatment ◽  
Medical Illness ◽  
Molecular Response ◽  
Hernial Repair

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm (MPN) that harbors the Philadelphia chromosomal translocation resulting in the uncontrolled production of mature granulocytes. Commonly, patients are diagnosed with CML during blood work for other reasons or enlarged spleen. The diagnosis is based on WHO criteria that require the demonstration of Philadelphia chromosome. Typically, <i>JAK2</i> mutation is not found in <i>BCR-ABL1</i>-positive MPN (CML). Most patients with CML are <i>JAK2</i> negative. It is rare for CML Philadelphia-positive patients to have a coexisting <i>JAK2</i> mutation. Little is known regarding the effect of <i>JAK2</i> mutation on the disease course of CML, the complications, and the response to treatment. We report the case of a 57-year-old man with no previous medical illness who presented with elevated white blood cell count on perioperative assessment for hernial repair; on further workup, he was diagnosed with Philadelphia-positive CML. He was found to have <i>JAK2</i> mutation and was started on treatment with dasatinib and achieved hematological and cytogenetic remission with loss of the <i>JAK2</i> mutation. Patients with <i>JAK2</i>-positive <i>BCR-ABL</i>-positive CML had a good hematological and cytogenetic response to dasatinib. In such rare coexistence of <i>JAK</i> and <i>BCR-ABL</i>, dasatinib is a good option due to multi-kinase activity.

“Real-life” Frontline Dasatinib Treatment in Unselected Elderly Patients with Chronic Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5530-5530
Author(s):  
Roberto Latagliata ◽  
Fabio Stagno ◽  
Mario Annunziata ◽  
Elisabetta Abruzzese ◽  
Alessandra Iurlo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Real Life ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Response To Treatment ◽  
Elderly Subjects ◽  
Molecular Response ◽  
Few Data

Abstract Background Dasatinib has been recently licensed for first line treatment of patients with chronic myeloid leukemia (CML). However, very few data are available as to toxicity and efficacy of dasatinib in unselected elderly CML patients. Aim To address this issue, we revised a “real-life” cohort of 43 CML patients in chronic phase aged > 65 years treated with frontline dasatinib in 19 Italian Centers from 6/2012 to 6/2014 focusing on toxicity and efficacy data. Methods The main clinical features of the patients at diagnosis were as follows: M/F 20/23 (46.5%/53.5%), median age 75.2 years [interquartile range (IQR) 70.3 – 79.8), median Hb 12.5 g/dl (IQR 11.0 – 13.7), median WBC 57.7 x 109/l (IQR 29.5 – 100.0), median PLTS 466 x 109/l (IQR 249 – 758). According to Sokal risk classification, 3 patients (6.9%) were low risk, 26 (60.4%) intermediate risk, 10 (23.2%) high risk while 4 (9.5%) were not classificable. 20/43 patients (46.5%) had ≥ 2 comorbidities requiring concomitant therapies: according to ECOG scale, performance status at baseline was 0 – 1 in 36 patients (83.7%) and 2 in 7 patients (16.3%). Results Median interval from diagnosis to dasatinib start was 23 days (IQR 14 – 32). Dasatinib starting dose was 140 mg/day in 1 patient (2.3%), 100 mg/day in 33 patients (76.7%) and < 100 mg/day in 9 patients (21.0%), respectively. After a median period of treatment of 9.7 months (IQR 4.3 – 17.5) all patients were evaluable for toxicity; on the whole, grade 3 – 4 hematological and extra-hematological toxicities were reported in 4 (9.3%) and 6 (13.9%) patients, respectively. Overall, 7 patients (16.2%) permanently discontinued dasatinib due to toxicity (2 patients in the first 3-month period of treatment and 5 beyond that period). Pleural effusions of all WHO grades occurred in 7 patients (16.2%): in 2 of them the pleural effusion occurred during the first 3-month period of treatment. As to treatment efficacy, 6 patients were considered too early to be evaluated (< 3 months of treatment) and 37 were evaluable for cumulative response; on the whole, 33/37 patients (89.1%) achieved complete cytogenetic response (CCyR) and 23/37 (62.1%) also a major molecular response (MMolR). Response to treatment at different time-points is shown on Table.3rd month6th month12th monthNot evaluable: Too early Not performed11651311219190Evaluable323024Discontinuation2 (6.2%)4 (13.3%)6 (25%)Less than CCyR6 (18,7%)2 (6.7%)0CCyR only17 (53.1%)5 (16.6%)4 (16.6%)MMolR7 (21.9%)19 (63.3%)14 (58.4%) Conclusions Present data shows that dasatinib could have a major role in the treatment of unselected patients aged > 65 years; indeed, dasatinib seems very effective and has a favourable safety profile also in elderly subjects with comorbidities. Disclosures Latagliata: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy. Gugliotta:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy.

scholarly journals European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Blood ◽  
2013 ◽  
Vol 122 (6) ◽  
pp. 872-884 ◽  
Author(s):  
Michele Baccarani ◽  
Michael W. Deininger ◽  
Gianantonio Rosti ◽  
Andreas Hochhaus ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Optimal Response ◽  
Frequent Monitoring ◽  
Leukemia Treatment

Abstract Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

Comparison Between Patients With Philadelphia-Positive Chronic Phase Chronic Myeloid Leukemia Who Obtained a Complete Cytogenetic Response Within 1 Year of Imatinib Therapy and Those Who Achieved Such a Response After 12 Months of Treatment

2006 ◽  
Vol 24 (3) ◽  
pp. 454-459 ◽  
Author(s):  
Ilaria Iacobucci ◽  
Gianantonio Rosti ◽  
Marilina Amabile ◽  
Angela Poerio ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Overall Survival Rates

Purpose Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein critical for the pathogenesis of chronic myeloid leukemia. Patients and Methods We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) –positive chronic myeloid leukemia treated with imatinib 400 mg daily after interferon-α failure. In a retrospective study, we evaluated the pattern and rapidity of the response to imatinib, comparing the cytogenetic and molecular responses, progression-free and overall survival rates in patients who obtained a complete cytogenetic response within 1 year of treatment (early responders), and in patients where a complete cytogenetic response was detected after 12 months (late responders). Results After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was similar to that of the early cytogenetic responders. At 36 months of treatment the amount of residual disease measured by standardized quantitative reverse-transcriptase polymerase chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48 months it was 0.00019 versus 0.00026 (median values, P value = nonsignificant). The estimated 4-year progression-free survival rate was 88% for early responders and 100% for late responders, while the estimated 4-year overall survival rates were 92% and 100% for early and late responders, respectively. Conclusion The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or more. Long-term follow-up results continue to improve in terms of rates and durability of the complete cytogenetic response, major or complete molecular response, and progession-free and overall survival.

scholarly journals Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4567-4576 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant

Abstract Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

scholarly journals Pathological Fracture: An Unusual Presentation in Childhood Chronic Myeloid Leukemia

2019 ◽  
Vol 13 (4) ◽  
pp. 140
Author(s):  
Mururul Aisyi ◽  
Ayu Hutami Syarif ◽  
Anita Meisita ◽  
Agus Kosasih ◽  
Achmad Basuki ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pathological Fracture ◽  
Hematological Malignancy ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Invasive Treatment ◽  
Non Invasive ◽  
Blast Count

Introduction: Chronic Myeloid Leukemia is a hematological malignancy driving from myeloproliferative process. It is typified by the presence of the Philadelphia chromosome manifesting in certain distinct complications, including pathological fracture. Pathological fracture is recognized as an extramedullary disease that occurs as a result of transformation of CML into blast crisis phase.Case Presentation: Here, we report a case of pediatric male CML. After being failed with imatinib therapy, he turned to nilotinib and was unable to achieve a major molecular response. He presented with high blast count and pain in the left arm. He was diagnosed with pathological fracture and blast crisis phase CML. Taken the young age and displacement of fracture into consideration, he was conservatively treated by a combination of immobilization and a higher dose of targeted therapy, nilotinib. The 2-month evaluation revealed clinical union and reduction of blast cells.Conclusions: Regarding the minimal displacement and age presentation, pathological fracture in pediatric CML requires non-invasive treatment and optimization of antileukemic therapy.

scholarly journals Organic Nanoparticles as Drug Delivery Systems and Their Potential Role in the Treatment of Chronic Myeloid Leukemia

2019 ◽  
Vol 18 ◽  
pp. 153303381987990 ◽  
Author(s):  
Mohammed Hussein Kamareddine ◽  
Youssef Ghosn ◽  
Antonios Tawk ◽  
Carlos Elia ◽  
Walid Alam ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Drug Delivery Systems ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Delivery Systems ◽  
Treatment Modalities ◽  
Organic Nanoparticles

Chronic myeloid leukemia is a myeloproliferative neoplasm that occurs more prominently in the older population, with a peak incidence at ages 45 to 85 years and a median age at diagnosis of 65 years. This disease comprises roughly 15% of all leukemias in adults. It is a clonal stem cell disorder of myeloid cells characterized by the presence of t(9;22) chromosomal translocation, also known as the Philadelphia chromosome, or its byproducts BCR-ABL fusion protein/messenger RNA, leading to the expression of a protein with enhanced tyrosine kinase activity. This fusion protein has become the main therapeutic target in chronic myeloid leukemia therapy, with imatinib displaying superior antileukemic effects, placing it at the forefront of current treatment protocols and displaying great efficacy. Alternatively, nanomedicine and employing nanoparticles as drug delivery systems may represent new approaches in future anticancer therapy. This review focuses primarily on the use of organic nanoparticles aimed at chronic myeloid leukemia therapy in both in vitro and in vivo settings, by going through a thorough survey of published literature. After a brief introduction on the pathogenesis of chronic myeloid leukemia, a description of conventional, first- and second-line, treatment modalities of chronic myeloid leukemia is presented. Finally, some of the general applications of nanostrategies in medicine are presented, with a detailed focus on organic nanocarriers and their constituents used in chronic myeloid leukemia treatment from the literature.

Molecular Monitoring and Mutations in Chronic Myeloid Leukemia: How to Get the Most out of Your Tyrosine Kinase Inhibitor

2014 ◽  
pp. 167-175 ◽  
Author(s):  
Michele Baccarani ◽  
Simona Soverini ◽  
Caterina De Benedittis
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Sanger Sequencing ◽  
Mutational Analysis ◽  
Residual Disease ◽  
Kinase Domain ◽  
Response To Treatment ◽  
Molecular Response ◽  
Therapeutic Decisions

The course of chronic myeloid leukemia (CML) and the response to treatment with tyrosine kinase inhibitors (TKIs) are best monitored and assessed using two molecular tests: the first is real-time quantitative reverse transcription-polymerase chain reaction (RQ-PCR), which measures the size of residual disease that is expressed as BCR-ABL1% (the ratio between BCR-ABL1 and a control gene) and the other is mutational analysis by Sanger sequencing, which checks for the presence of BCR-ABL1 kinase domain point mutations. Both tests are technically demanding and require a high level of specialization and standardization. RQ-PCR, when performed on a regular basis, allows for the defining of molecular response (MR) levels as log reduction from a standardized baseline: major molecular response (MMR or MR3) that is the best predictor of survival; and the deeper molecular response (MR4, MR4.5, and MR5) that is necessary to enroll a patient in a trial aiming at treatment-free remission (TFR). Mutational analysis, to be performed in case of failure or warning by Sanger sequencing, allows for screening of the BCR-ABL1 kinase domain for mutations conferring resistance to TKIs. Since different mutations have different degrees of sensitivity to each of the currently available TKI, the knowledge of BCR-ABL1 kinase domain–mutation status is necessary for subsequent treatment choice. Optimal patient management requires that MR and mutational information be rationally interpreted at both the technical and at the biologic level, and put into context—therapeutic decisions also take into account other factors, such as age, comorbidities, side effects, compliance, and treatment-related complications.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1527-1535 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Antonio de Vivo ◽  
Francesca Bonifazi ◽  
Domenico Russo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Arabinosyl Cytosine

Interferon-α (IFN-α) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-α has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome–positive CML patients who were assigned at random to treatment with IFN-α2a alone or in combination with LDAC. The scheduled dose of IFN-α2a was 56IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-α–plus–LDAC arm versus 55% in the IFN-α arm; P = .11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-α versus IFN-α plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

scholarly journals Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1141-1145 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis J. Giles ◽  
Kapil N. Bhalla ◽  
Javier Pinilla-Ibarz ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Molecular Response ◽  
Open Label ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase

Abstract Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.

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