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.
Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.
The introduction of imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid leukemia (CML). Although experience is too limited to permit evidence-based evaluation of survival, the available data fully justify critical reassessment of CML management. The panel therefore reviewed treatment of CML since 1998. It confirmed the value of IM (400 mg/day) and of conventional allogeneic hematopoietic stem cell transplantation (alloHSCT). It recommended that the preferred initial treatment for most patients newly diagnosed in chronic phase should now be 400 mg IM daily. A dose increase of IM, alloHSCT, or investigational treatments were recommended in case of failure, and could be considered in case of suboptimal response. IntroductionAfter the initial descriptions of chronic myeloid leukemia (CML) more than 150 years ago, little meaningful progress was made in its treatment for more than a century. Radiation therapy and busulfan contributed more to improving quality of life than to prolonging survival. Survival prolongation was first achieved with hydroxyurea (HU), much more with allogeneic hematopoietic stem cell transplantation (alloHSCT) and, later, in a minority of patients, with recombinant interferon-alpha (rIFN␣). 1 Understanding the pathogenesis of the disease began with the discovery of the Philadelphia (Ph) chromosome followed by appreciation of its molecular counterpart, the BCR-ABL fusion gene. 2,3 Recognition of the tyrosine kinase (TK) activity of the Bcr-Abl proteins led to the discovery of a new series of compounds targeted against BCR-ABL-encoded proteins, which inhibited the TK activity, thus aborting the signals controlling the leukemic phenotype. 4 One of the TK inhibitors, imatinib mesylate (IM), was found to have a high and relatively specific biochemical activity and an acceptable pharmacokinetic and toxicity profile, and was thus rapidly introduced into clinical practice. [5][6][7] This resulted in a revolutionary step in the management of CML and by extension a shift in paradigm for the management of cancer in general.The most recent comprehensive analysis of CML treatment was an evidence-based guideline developed in 1998 by an expert panel convened by the American Society of Hematology (ASH) covering conventional chemotherapy, rIFN␣, and alloHSCT. 8 TK inhibitors were not considered at that time but were subsequently the subjects of editorials and preliminary reviews. 7,[9][10][11][12][13][14] Although it is premature at this time to perform an evidence-based analysis of the effects of IM, the implications and consequences of the introduction of TK inhibitors are so important that it is not too early to review the available data and to discuss how the treatment of CML could be managed and further progress could be pursued based upon expert opinion. Therefore, the European LeukemiaNet appointed a panel of experts to review the current situation. This report constitutes its opinion. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From Methods Panel compos...
We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first-and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.
Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a Ͼ10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.
The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n ؍ 28), chronic or acute myeloid leukemia (n ؍ 35), secondary erythrocytosis (n ؍ 4), or healthy controls (n ؍ 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. IntroductionChronic myeloproliferative diseases (CMPDs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages in the bone marrow and increased numbers of mature and immature cells in the peripheral blood. CMPDs include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML), plus rarer subtypes such as chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), and chronic eosinophilic leukemia (CEL). These diseases overlap with myelodysplastic/myeloproliferative diseases (MDS/MPDs) such as atypical CML (aCML) and chronic myelomonocytic leukemia (CMML), in which proliferation is accompanied by dysplastic features or ineffective hematopoiesis in other lineages. 1 We refer here broadly to all these groups as myeloproliferative disorders (MPDs).Although there are strict diagnostic criteria for MPD subtypes, precise categorization remains a subject of debate 2 and furthermore, it can be difficult to differentiate some cases from reactive disorders. Only CML is characterized by a pathognomonic molecular marker, the BCR-ABL fusion, and the primary abnormalities driving excess proliferation in most other cases have been obscure. However, several lines of evidence have implicated aberrant tyrosine kinase signaling as the root cause of MPDs. Breakpoint cluster region-abelson (BCR-ABL) itself is a constitutively active tyrosine kinase that is believed to be the primary, and probably the only, driving force behind chronic-phase CML. 3 Other gene fusions have been identified in rare cases of aCML, CMML, and HES/CEL that involve the tyrosine kinases PDGFRA, PDGFRB, FGFR1, and JAK2. 4,5 In addition, the KIT receptor is activated by point mutation in the majority...
A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.
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