Blood Cancer Journal · 2017 · 54 citations · open access
Clinical and prognostic significance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leukemia
AbstractChronic myeloid leukemia (CML) is characterized by the presence of BCR-ABL1 fusion gene. In over 95% of CML patients, the typical BCR-ABL1 transcript subtypes are e13a2 (b2a2), e14a2 (b3a2) or expression of both simultaneously. Other less frequent transcript subtypes, such as e1a2, e2a2, e6a2, e19a2, e1a3, e13a3 and e14a3, have been sporadically reported. 1 Different subtypes of BCR-ABL1 transcripts encode fusion proteins with different sizes that may lead to different disease phenotypes. The e13a2 and e14a2 transcripts encode P210 BCR-ABL1 proteins with slightly different sizes. Patients with the e14a2 transcript have a significantly higher platelet count than those with the e13a2 transcript. 2 , 3 , 4 Patients with the e19a2 transcript, which encodes P230, often present with prominent neutrophilic maturation or thrombocytosis, whereas patients with the e1a2 transcript, which encodes P190, often present with monocytosis, absence of basophilia and a tendency to progress to lymphoid blast phase (BP). 5 , 6 , 7
https://doi.org/10.1038/bcj.2017.62American Journal of Hematology · 2011 · 6 citations · open access
Chronic myeloid leukemia 2011: Successes, challenges, and strategies—Proceedings of the 5th annual BCR‐ABL1 positive and BCR‐ABL1 negative myeloproliferative neoplasms workshop
AbstractThis report is based on the presentations and discussions at the 5th annual BCR-ABL1 positive and BCR-ABL1 negative myeloproliferative neoplasms (MPN) workshop, which took place immediately after the 52nd American Society of Hematology (ASH) meeting in Orlando, Florida on December 7th–8th, 2011. Relevant data which was presented at the ASH meeting as well as all other recent publications were presented and discussed at the workshop. This report covers frontline therapies of BCR-ABL1-positive leukemias, in addition to addressing some topical biological, preclinical and clinical issues, such as new insights into genomic instability and resistance to tyrosine kinase inhibitors (TKIs), risk stratification and optimizing molecular monitoring. A report pertaining to the new therapies and other pertinent preclinical and clinical issues in the BCR-ABL1 negative MPNs is published separately. For patients with BCR-ABL1-positive leukemias, which comprise of all the Philadelphia (Ph) chromosome-positive and some Ph-negative leukemias, the introduction of the original tyrosine kinase inhibitor (TKI), imatinib mesylate (IM) into the clinics in 1998, resulted in being a classic therapeutic landmark [1, 2]. After 12 months of therapy with IM, 69% of patients with CML-CP achieve a complete cytogenetic response (CCyR) and after 8 years of follow-up, such response rates increases to 83%. This remarkable activity translates into an estimated overall survival of 93% (when only CML-related deaths are accounted for), which is substantially higher than that achieved by any previous medical treatment, including allogeneic stem cell transplantation (allo-SCT) [1, 2, 3]. The success in the treatment of patients with CML in advanced phases and the Ph-positive acute lymphoblastic leukemia (ALL) has also been improved with the addition of IM to cytotoxic drugs, though less remarkably [4, 5]. The adverse events attributable to IM appear to be relatively mild, but not innocuous, and generally easily manageable [6, 7]. Conversely, about 35% of all patients with CML-CP and substantially higher proportions with CML in advanced phases and Ph-positive ALL cannot tolerate IM or have a leukemia that becomes resistant or refractory to IM. Recent observations suggest that about 18% of IM-treated patients do not achieve a CCyR, and 10% who do will lose such response over time. Furthermore about 26% of patients are intolerant of IM [6]. Novel risk stratification methods and optimal molecular monitoring can be used to judge response and predict future risk of progression for patients with CML-CP. These are complemented by recent insights into the mechanisms of resistance to TKIs as well as by knowledge gained regarding aspects of the cellular and molecular biology of BCR-ABL1-positive cells, such as their underlying genomic instability. Given the limited activity of TKI therapy in advanced phases of the disease, the most immediate goal of CML therapy is the prevention of progression, which has been associated with the achievement of deep responses at early time points during the course of TKI therapy. In this regard, the use of second-generation TKIs (i.e., nilotinib, dasatinib, bosutinib) as frontline therapy has led to an increase in the number of patients capable of achieving CCyR during the first year of therapy. The activity of these agents as frontline therapy for patients with CML-CP has been tested in a series of ongoing randomized, multicenter: nilotinib (ENESTnd), dasatinib (DASISION and Intergroup Trial SO325), and bosutinib [8-10]. Both dasatinib and nilotinib have been recently approved for frontline use for patients with CML-CP in many other countries around the world; dasatinib is also approved for Ph-positive ALL in USA and Switzerland. Both of these drugs are more potent BCR-ABL1 inhibitors with demonstrated efficacy in patients resistant to or intolerant of imatinib and are active against most BCR-ABL1 mutations, with the notable exception of the T315I mutation [11, 12]. The increased potency, and a safety profile which so far appears to be equivalent if not better than that of IM, further supports the use of these drugs as frontline treatment for patients with CML-CP. Bosutinib, while still not approved as a CML therapy, has been recently shown promising activity in both the frontline and the post-imatinib failure settings. Looking ahead, other novel agents, such as ponatinib and DCC-2036, are being assessed for the treatment of patients carrying the T315 mutation, as well as for those who have failed therapy with more than two TKIs [13-15]. As novel TKIs are added to the CML armamentarium, the frontline treatment algorithm for patients with this malignancy needs to be reassessed. Furthermore, IM is rapidly approaching the end of its patent life, a fact that will undoubtedly factor into the treatment decision making process. Ongoing efforts are assessing the potential role of generic IM. The enormous clinical success of TKI therapy has turned CML into a truly chronic disease, as a recent study found that CML patients who achieve CCyR within 2 years on IM have an overall survival rate that is no different from the general population [16]. This, in turn, predicts that the population of CML patients in the U.S. will exceed 250,000 by 2040. The ultimate goal of oncologists is to cure cancer, and the focus of much of basic and preclinical CML research has now turned to this area. We now recognize that TKI therapy is not curative in the majority of CML patients, as results from the French STIM study demonstrate that over half of CML patients in complete molecular remission (CMR) on imatinib relapse quickly when TKI therapy is stopped [17]. It is postulated, but not proven, that these relapses are a consequence of quiescent CML stem cells that are resistant to killing by conventional TKIs [18]. Indeed, these malignant progenitors can be detected in bone marrow (BM) from CML patients in CCyR on IM [19]. Results presented at the 2010 American Society of Hematology (ASH) meeting demonstrated that BCR-ABL1 positive clonogenic progenitors, including Long-term culture-initiating cells (LTCIC), can also be found in CML patients in CMR [20], whose disease is undetectable by conventional RT-PCR. Hence, there is much current interest in identifying targets and strategies for eliminating leukemic stem cells (LSC) in CML. At the 2010 ASH meeting, several groups reported on using next-generation and deep sequencing technologies to interrogate CML patient genomes to identify new pathogenetic targets in CML. Comparative whole transcriptome sequencing of a CML patient who progressed to myeloid blast crisis identified eight missense mutations in novel genes, including IDH2 and protein kinase D2 [21]. Deep sequencing of 40 blast crisis CML patients (25 myeloid, 10 lymphoid, 5 unspecified) revealed frequent IKZF1, RUNX1, and ASXL1 mutations that developed during disease progression [22]. Further studies will be necessary to determine the role of these mutations in disease progression and assess their suitability as targets for therapy. Additional research efforts focused on specific signaling pathways that might represent targets for elimination of LSCs in CML. BCL6, a zinc finger protein that functions as a proto-oncogene in diffuse large B cell lymphoma, was shown to be required for maintenance of CML stem cells in the retroviral mouse model, and incubation of human CML progenitors with a peptide BCL6 inhibitor decreased engraftment of immunodeficient NSG mice [23]. Stearoyl-CoA desaturase 1 (Scd1), an endoplasmic reticulum enzyme catalyzing the biosynthesis of monounsaturated fatty acids from saturated fatty acids, was identified as a potential tumor suppressor gene in CML stem cells, as CML-like leukemia induced from Scd1−/− BM had higher levels of functional LSCs, whereas treatment of leukemic mice with the PPARγ agonist rosiglitazone increased Scd1 expression and decreased LSCs previous studies have the in the maintenance of CML stem cells in mouse retroviral A recent study the of cells in a mouse of and demonstrated that treatment of mice with the inhibitor with the TKI nilotinib decreased CML LSCs in but not and further decreased engraftment of NSG mice with human CML progenitors Given the recent of clinical of in refractory Ph-positive further preclinical studies of these agents are to in their clinical The role of in the maintenance of stem cells in CML was also by several be by an or an of a These results the of in CML a specific or the study presented at ASH tested the activity of a novel and demonstrated that this stem cells from blast crisis CML in and in of and these basic and preclinical studies to CML as the human cancer, and the that will be to the leukemia and cure patients the for therapy. The goal of risk stratification is to patients with a higher risk of progression on current with CML-CP as a of resistance or progression can be more therapy, for the use of second-generation be in a clinical or be for In patients at risk be with for or more therapy if optimal response are not both the and were from clinical the appear to well in response to TKI therapy. At patients with CML with of time from BCR-ABL1 therapy, BCR-ABL1 signaling and instability. Furthermore, is that the the of time CML and TKI therapy, the the of molecular mutations, which to the more advanced phases of the The clinical and that as of time from disease are the and the cell the rate and which the and the increases different patients, these a of disease These and other clinical the for the blast and and risk which have been shown to be in response to TKI therapy but not TKI are the of drugs and by and IM can be by and by and In studies imatinib in cells by activity demonstrated that activity was associated with higher response rates molecular and mutation with patients whose cells had activity studies have that levels can be in a much and than IM also with response It is of interest that of the second-generation TKIs and is by the activity of be in levels for these two the of a with a response to while expression gene expression and pathways associated with The most of the of specific on response from the study of the of the In a study patients with those with a had higher imatinib levels and a higher of molecular the not demonstrate on imatinib levels groups have for associated with progression and resistance to TKI therapy in CML. The far there is a gene which is in advanced disease with The in gene expression during the from to are further in the from to blast there are gene and targets that targets for prevention of CML For progression is associated with of in the and the most in progression were and both of which are potential targets for cell appears to be in the in progression and has been shown to with This was to new patients in and advanced disease, as well as of CML and patients with that on IM therapy. The progression and with response to IM therapy in patients in (i.e., disease had a progression while of disease had a of CML who were resistant to IM had a progression further an of the biology of progression and resistance Further of the of this was demonstrated when was to patients with CML-CP The expression of the was in CML-CP and a was with a progression had a relapse rate of only while those with a a relatively had a relapse rate of This that gene expression can be from and that such might the of a relapse of response to TKI therapy is the of response at early time The have demonstrated that BCR-ABL1 levels assessed by after only months of therapy is associated with achievement of CCyR, molecular response and progression survival The of BCR-ABL1 by is most in patients that have achieved a After years of in the if patients achieving CCyR and at months has progressed to or The rate of progression for those that had a CCyR but less than in BCR-ABL1 was only studies have the data and demonstrate that patients with a molecular response at the time of CCyR, or a of BCR-ABL1 during CCyR, have of progression and a with patients with an response the be The BCR-ABL1 in a patient for a number of to in the of an (i.e., any and a patient with a molecular response in the of chronic the to a is results to in the of a tumor and the of the In most a in the is is not BCR-ABL1 levels in patients over time while on TKI therapy. CML is to have with and at and this has not been in with disease the and most for an increase in BCR-ABL1 is in BCR-ABL1 levels not any in therapy. of achieving or an increase in BCR-ABL1 levels be is an potent kinase the BCR-ABL1 and the success in the treatment of patients with CML-CP or intolerant to IM, the was approved for the treatment of all phases of CML with or to IM and all patients with Ph-positive was to most mechanisms of resistance to IM, with the exception of the T315I The an with IM for frontline therapy of patients with CML-CP A of such patients were into the in CML and the results were published in 2010 and presented an at the ASH meeting in December 2010 were to IM or dasatinib The of the study was CCyR at 12 were by risk which resulted in of and risk in of the to IM and to dasatinib was for patients with After a of more patients required those with dasatinib with those IM the rates of CCyR were in those patients dasatinib therapy, both at 12 and at months At CCyR rates were with dasatinib with IM, to at rates by 12 months were higher with dasatinib with IM the of patients who achieved time to was months for dasatinib and months for IM. patients with dasatinib, only progressed to advanced CML with not those IM. these data were reported on an and patients were for to or for to after dasatinib any for were not as to which have the risk of in both of the After a of of patients to dasatinib while to IM therapy. was well with both with in of patients with dasatinib developed but only therapy for such of and were but more patients with dasatinib developed with those with IM the results reported by the studies suggest that frontline therapy with dasatinib higher response rates with a profile with IM. It these higher rates of early response will into improved no in have been the dasatinib and the imatinib The results from the study were also reported at the ASH meeting and the This was a study of imatinib at or in CML At 12 the CCyR and rates were for imatinib for the the success in studies assessing the role of nilotinib, an TKI and to IM, the was in the frontline use in patients with CML in The and in is the only randomized, study the efficacy and safety of nilotinib with IM A of patients with CML in were to nilotinib nilotinib or IM The was at 12 and patients were by risk which resulted in of and risk in of the results were published in 2010 and presented at the ASH meeting in December a IM to was in the IM to that therapy was for patients with responses to IM. patients on study in both nilotinib for nilotinib for nilotinib than in the IM an the rate at 12 months was higher for nilotinib and nilotinib than for IM for patients the rates were higher for nilotinib and nilotinib than for IM an the rates of CCyR by 12 months were higher for nilotinib and than for IM for patients, the CCyR at 12 months was higher for nilotinib and nilotinib than for IM were rapidly achieved with nilotinib, with rates of and and rates of and 18% for nilotinib nilotinib and IM, patients achieved complete molecular responses with nilotinib and nilotinib than with IM These higher responses were also associated with with nilotinib than with IM. After months of follow-up, the to of nilotinib to demonstrate better responses with IM, and a overall survival was for nilotinib IM the for nilotinib in the is and not It is also of interest that in this patients on the nilotinib who were were study the study not for a of nilotinib to patients study and an a was In therapy was well in all the study and treatment to adverse events was in and of patients on nilotinib nilotinib and IM, was more in the nilotinib with IM who more and with nilotinib such as levels of and were less than those reported in 2 nilotinib there were no of in any of the nilotinib were reported in of the study patients, with the exception of which was in of the nilotinib is a next-generation TKI with a of the and The appears to activity against or making less to be associated with studies assessing role in the treatment of patients with CML-CP intolerant or to IM, the an randomized, to its role in the frontline with IM In the patients with CML-CP intolerant or to IM were and of the patients were to have achieved a CCyR The were and and was also to a of mutations associated with IM but not the T315I The results from a frontline study the activity and of imatinib were presented at the 52nd ASH meeting The study patients with CML-CP. that at 1 the was with bosutinib 26% with IM The study failed to its of CCyR with bosutinib at 1 for bosutinib for IM, a that was not at 1 treatment failure rates were on the bosutinib with 10% on the IM In this bosutinib was associated with more and with the most frequent and adverse events were and bone and were associated with IM therapy. was reported in of patients with bosutinib and of those IM. has also been tested as a in an study of patients with CML-CP intolerant or to IM and a second-generation TKIs A of patients were in this At 26% of patients achieved a including with the CCyR rate was The profile to be to that in with the exception of which was in of These results that bosutinib is active in a of patients who have failed approved TKIs in CML-CP. The introduction of in dasatinib, for the treatment of patients with CML in advanced phases and Ph-positive ALL has improved the response rates and the of these patients these patients have and remission and only be to a of patients who were for an IM a of success in this but most patients still to the disease to of response and of resistance In a of patients with Ph-positive ALL kinase mutations after an response to IM of IM IM have shown a better cytogenetic response rates with the of IM or the second-generation TKI dasatinib, with cytotoxic has to be more in patients with Ph-positive ALL with a number of recent that and survival with that by be with such recent studies have dasatinib during and maintenance for patients with or Ph-positive ALL In a patients with Ph-positive ALL and patients with CML in blast crisis were responses were in of patients, with achieving was in and CMR in In the Ph-positive ALL the the efficacy and safety of dasatinib or for the first of of eight of and and who achieved a complete remission maintenance dasatinib and and for 2 by dasatinib A of patients with Ph-positive ALL with a of years were At the time of the in of patients achieved a complete a of months the estimated survival was These results are promising not from those at the with in with Further is to the role of dasatinib in the of patients with Ph-positive At patients with this disease are still to in first complete remission in to IM and nilotinib, is to the and an with other TKIs regarding the prevention of relapse patients with CML in advanced phases and Ph-positive ALL to or lose their response as a consequence to kinase the in patients with Ph-positive ALL is the T315I mutation, which is resistant to all The of such patients is and many efforts are now assessing a number of drugs in this such is ponatinib as a inhibitor of BCR-ABL1 that both active and of the enzyme and is active against a of BCR-ABL1 as well as other such as and In cellular the of ponatinib against T315I BCR-ABL1 is in to and for IM, nilotinib, and dasatinib, The of the first 1 study of this was reported during the 52nd ASH meeting patients including with CML and 8 with and disease, with Ph-negative ALL and with other were The treatment for the patients with Ph-positive were IM in dasatinib in and nilotinib in with and two or more TKIs or or more The T315I mutation was in of patients with a of other mutations in other patients including 26% with no The of ponatinib was from to and and was as the for 2 studies with the being of and of patients at had as patients with Ph-positive leukemia were for patients with CML in had complete response and had cytogenetic response 12 CCyR, 8 CML-CP cytogenetic on treatment progression, and two patients at and progressed after CML-CP patients with T315I mutation, had had patients with advanced CML or Ph-positive had response had had patients with advanced CML or Ph-positive ALL with the T315I mutation, had two had were also in refractory patients with no mutations as well as in those carrying a of of patients with Ph-positive leukemia achieved including patients with with T315I mutation at with demonstrated of The that ponatinib has an safety profile at therapeutic A 2 study is the activity of this in Ph-positive the TKIs in clinical use dasatinib, and the majority of leukemia cells in patients to the treatment, their on LSCs is with CML-CP leukemia cells resistance to imatinib These cells resistance to TKIs and progression to TKI resistance be induced not only by mutations in the kinase of BCR-ABL1 but also by mutations in other from the BCR-ABL1 kinase and by different TKI resistant BCR-ABL1 kinase appear to be more to which their to into more malignant As genomic revealed number of in but CML-CP cells The that genomic instability in CML is an early TKI resistant mutations in BCR-ABL1 kinase and have been detected not only in but also in LSCs that genomic instability at the of detected in LSCs are to be of instability results from mechanisms of from which can to all and and CML cells about more and more than of in CML cells appears to be a of genomic instability to and the of the BCR-ABL1 kinase levels of with activity to of mutations in CML cells, including these in BCR-ABL1 kinase TKI resistant can also that represent a and to survival and genomic BCR-ABL1 kinase all mechanisms of and to genomic instability. In leukemia cells, mutations, resulted in more in some and large but which are for malignant progression of CML. In CML-CP LSCs levels of and which these cells into TKI resistant with an increased potential for progression to The of all BCR-ABL1 positive has been by the introduction of TKI therapy, which rates of CCyR that into and rates of and TKIs such as dasatinib and nilotinib CCyR and at higher rates and at a much than IM. the of studies the use of second-generation TKIs used in the frontline is and the higher response rates will into improved is results demonstrate a or a at 12 months in the rates of from progression in the in the and the in the with the IM-treated be from some of the from the and other with to the and of a specific therapy These are discussed in a recent report by These also the of the in study the results are and more the of different in and CCyR in which are at time only a of patients in the have been to The study reported rates 12 months of for nilotinib while the reported rates 12 months for dasatinib of It is that patients who have the response or treatment 12 months not be in the but be as in the For in the rate for nilotinib was 12 which an increase of in the rate by such response rates in a Furthermore, the results reported in these studies are after a of or not after a of or the of such A further of be by the that the of the more both CCyR and in the recent dasatinib and nilotinib frontline are This is by of the the of achieving at 12 months in to which with that the of such of response at the time As efforts in on the frontline therapies can an in the progression and resistance to TKI risk is based on the These of of different levels of that in studies whole and gene In the of sequencing new or which disease the BCR-ABL1 molecular monitoring by is and conventional In the will still be to new associated with advanced disease whole sequencing becomes and BCR-ABL1 on will be used to disease, which only in of response or both demonstrated by Recent such as the French STIM suggest the that achieving a CMR predict for of response and be used to TKI therapy The STIM and other recent studies suggest that in about of patients who achieve a IM be Conversely, about of patients relapse at a molecular within months of IM being This CMR an to both clinical and molecular methods will to more the of identifying patients with CMR those CMR by the This the further efforts to achieve CMR and disease and treatment It is to that such a represent a for patients with CML-CP. The and the and for the 5th ASH on CML and and for the of for the of for and for and
https://doi.org/10.1002/ajh.22097