Management Of Chronic Myeloid Leukemia-Books Pdf

Management of Chronic Myeloid Leukemia
29 Jan 2020 | 77 views | 0 downloads | 32 Pages | 651.19 KB

Share Pdf : Management Of Chronic Myeloid Leukemia

Download and Preview : Management Of Chronic Myeloid Leukemia


Report CopyRight/DMCA Form For : Management Of Chronic Myeloid Leukemia



Transcription

CLINICAL PRACTICE GUIDELINE LYHE 001,BACKGROUND, Chronic myelogenous leukemia CML is a disease characterized by the expression of BCR. ABL an oncogenic tyrosine kinase that induces bone marrow stem cell proliferation Untreated. there is progression from a relatively benign chronic phase lasting 3 to 5 years to a rapidly fatal. acute leukemia blast crisis Impressive therapeutic advances in the management of CML have. occurred in the past two decades starting with the introduction of the tyrosine kinase inhibitor. TKI imatinib which dramatically improved survival in a large proportion of patients and then. introduction of second and third generation TKIs namely nilotinib dasatinib bosutinib and. ponatinib for patients with imatinib resistance or intolerance Nilotinib and Dasatinib have now. been approved in Alberta along side Imatinib as first line agents for patients newly diagnosed. with CML Other novel agents remain under investigation Allogeneic hematopoietic stem cell. transplantation is also available for selected patients with CML but is rarely utilized. GUIDELINE QUESTIONS, What diagnostic and baseline investigations are recommended for adult patients with. suspected or confirmed CML, What are the recommended treatment options for CML. What are the criteria for monitoring response to treatment. DEVELOPMENT, Portions of this guideline document were adapted with permission from recommendations. developed and updated by the Canadian Consensus Group on the Management of Chronic. Myelogenous Leukemia This guideline document was reviewed and endorsed by the Alberta. Provincial Hematology Tumour Team Members of the Alberta Provincial Hematology Tumour. Team include hematologists medical oncologists radiation oncologists surgical oncologists. nurses pathologists pharmacists and a knowledge management specialist from the Guideline. Resource Unit A detailed description of the methodology followed during the guideline. development process can be found in the Guideline Resource Unit Handbook. SEARCH STRATEGY, In 2012 the recommendations developed by the Canadian Consensus Group on the.
Management of Chronic Myelogenous Leukemia were converted to an Alberta guideline based. closely on the European Leukemia Net Guidelines 1 In addition guidelines developed by. Cancer Care Ontario CCO European Society for Medical Oncology ESMO National. Comprehensive Cancer Network National Institute for Health and Clinical Excellence NICE. were reviewed in the process of developing this document Appendices A B and C summarize. the most current recommendations from these agencies. The 2015 and 2017 updates incorporated new evidence from research involving tyrosine kinase. inhibitors for the treatment of CML along with general updates. TARGET POPULATION, The following guidelines apply to adults over 18 years of age Different principles apply to. pediatric patients,Page2 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001. RECOMMENDATIONS,Staging and Prognosis, 1 Staging of CML according to the definitions set out by the World Health Organization. The chronic phase CP is defined by peripheral blood blasts fewer than 10 in the. blood and bone marrow, The accelerated phase AP is defined as any one or more of the following2. Persistent or increasing WBC 10x109 L unresponsive to therapy. Persistent or increasing splenomegaly unresponsive to therapy. Persistent thrombocytosis 1000x109 L unresponsive to therapy. Persistent thrombocytopenia 100x109 L unrelated to therapy. 20 or more basophils in the PB,10 19 blasts in the PB and or BM.
Additional clonal chromosomal abnormalities in Ph cells at diagnosis that include. major route abnormalities second Ph trisomy 8 isochromosome 17q trisomy 19. complex karyotype or abnormalities of 3q26 2, Any new clonal chromosomal abnormality in Ph cells that occurs during therapy. The terminal blast crisis BC phase is defined by peripheral blood myel o or lympho. blasts 20 of peripheral blood white blood cells or nucleated bone marrow cells. extramedullary blast proliferation and large foci or clusters of blasts on bone marrow. 2 The Sokal index and or Hasford score are recommended for prognostication of newly. diagnosed patients with CML 3 The European Treatment and Outcome Study EUTOS. score 3 4 can be used for patients being treated with a TKI to predict complete cytogenetic. response CCyR at 18 months The new ETLS differentiated probabilities of dying of CML. better than the Sokal Euro and the European Treatment and Outcome Study EUTOS. score showed higher age more peripheral blasts bigger spleen and low platelet counts. are significantly associated with increased probabilities of dying of CML Using these. factors the scoring system stratifies patients into 3 risk categories low 61 of patients. intermediate 27 of patients high 12 of patients based on probability of CML. related death and of overall survival Low risk patients are anticipated to have very. promising long term outcomes when starting imatinib117 An online calculator is available. Diagnosis and Baseline Investigations, 3 The following investigations are recommended at diagnosis for all patients with suspected. or confirmed CML,CBC and differential,Bone marrow aspirate and biopsy. Baseline bone marrow cytogenetics, Peripheral blood or bone marrow quantitative real time polymerase chain reaction. Liver function tests lipase glucose urate cholesterol fasting glucose HgbA1c. lipid panel,Treatment Options, 4 Treatment with a TKI as first line treatment for all newly diagnosed CP CML patients is.
recommended as the early response to a TKI can either reinforce or weaken the indication. Page3 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, for allogeneic SCT Currently in Alberta therapy is begun with imatinib dasatinib or. nilotinib The choice of TKI may be guided by an individual patient s comorbidities. Patients having achieved their therapeutic milestones with and tolerant of imatinib should. continue on it Hydroxyurea is useful in controlling leukocytosis and thrombocytosis while. waiting for results of BCR ABL test results Allopurinol should be administered for. prevention of hyperuricemia complications, 5 A second generation TKI nilotinib or dasatinib is recommended for patients with imatinib. resistance intolerance or who fail to achieve any of the treatment milestones while on. imatinib The choice of a second generation TKI may be guided by an individual patient s. comorbidities The presence of specific mutations will override other considerations when. determining the optimal agent to employ Patients eligible for transplant should be. evaluated for possible transplantation given the lack of long term efficacy data for second. generation agents Bosutinib is available in patients for whom Imanitib Nilotinib or. Dasatinib are not appropriate due to intolerance or comorbidities The third generation. drug Ponatinib is also available in the appropriate patient with a T315I mutation via. director s privilege, 6 Allogeneic stem cell transplant SCT remains a treatment option as it is the only known. cure this option may be selected at any point during the treatment course based on. informed patient preference Allogeneic SCT is the preferred option in patients with. evidence of clonal progression or with advanced phase disease The most effective. treatment available should be employed while awaiting transplantation. 7 All transplant eligible patients who fail second line TKI therapy should be evaluated for. transplantation before treatment with a third line TKI is considered Transplantation should. be considered in patients with evidence of clonal progression by bone marrow. cytogenetics, 8 Patients presenting with accelerated phase disease should be started on a TKI with early. consideration given to transplantation, 9 Patients presenting with blast phase disease should be treated with induction type.
chemotherapy along with a TKI and early consideration should be given to transplantation. 10 Interferon IFN should be considered only in patients who are unable to tolerate a TKI. and are ineligible for SCT or entry in a clinical trial or in women who wish to become. pregnant Treatment should be employed with the guidance of a physician with clinical. experience using IFN,Monitoring Treatment Response. 11 Peripheral blood Q RT PCR should be performed every 3 months If a molecular. response greater than 3 log reduction MMR is reached and stable for 2 years the. frequency of Q RT PCR may be decreased to every 4 6 months Bone marrow. karyotyping may be employed as an alternative to Q RT PCR until CCyR 1 IS is. achieved Bone marrow karyotyping may be performed at 1 year to confirm CCyR and to. detect clonal progression or other abnormalities Thereafter marrow karyotyping should. not be performed annually unless there are clonal abnormalities that need to be followed. 14 The recommended definition of first line optimal treatment response to tyrosine kinase. inhibitors TKIs in accordance with European Leukemia Net guidelines are defined as. Page4 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, BRC ABL1 10 at least a 1 log reduction and or Ph 35 at 3 months. BRC ABL1 1 2 log reduction and or Ph 0 at 6 months. BRC ABL1 0 1 3 log reduction at 12 months and thereafter. 15 The recommended definition of treatment failure on first line TKIs in accordance with. European Leukemia Net guidelines are defined as,Non CHR and or Ph 95 at 3 months. BCR ABL1 10 and or Ph 35 at 6 months,BCR ABL1 1 and or Ph 0 at 12 months. Thereafter loss of CHR CCyR or confirmed loss of mutations CCA Ph or MMR on. two consecutive tests of which BCR ABL1 transcripts level 1 in at least 1 test. 12 Compliance to TKI prescription should be assessed at every visit particularly in. those patients with a suboptimal response, 13 Mutation testing is recommended in patients who fail to achieve treatment milestones or if.
there is a loss of response Mutational analysis should always be performed before. switching TKIs, 14 Human leukocyte antigen HLA typing of the patient and siblings is recommended when a. patient presents in AP or BC or when there is suboptimal response loss of a previously. obtained response or significant intolerance, 15 Repeat cytogenetic and mutation testing after treatment with a second line TKI are. advised if no improvement in therapeutic milestones or a loss of response is observed. 16 Second line optimal treatment response to TKI after failure with imatinib in accordance. with European Leukemia Net guidelines are defined as. BCR ABL1 10 at least 1 log reduction and or Ph 65 at 3 months. BCR ABL1 10 at least 1 log reduction and or Ph 35 at 6 months. BCR ABL1 1 2 log reduction and or Ph 0 at 12 months. BCR ABL1 0 1 3 log reduction thereafter, 17 Second line treatment failure with a second generation TKI in accordance with European. Leukemia Net guidelines are defined as,No CHR or Ph 95 at 3 months. BCR ABL1 10 and or Ph 65 and or new mutations at 6 month. BCR ABL1 10 and or Ph 35 and or new mutations at 12 months. Thereafter loss of CHR CCyR PCyR or new mutations or confirmed loss of CCA Ph. or MMR in 2 consecutive tests of which one with a BCR ABL transcripts level 1. 18 Cardio vascular risk factors should be optimized in all patients on TKI therapy. given their emerging side effect profiles HgbA1c and lipid panels should be. monitored yearly, 19 Discontinuation of TKI therapy in responding patients is not recommended outside.
of a clinical trial,Page5 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001. DISCUSSION, Members of the Alberta Provincial Hematology Tumour Team recommend staging of CML. according to the definitions set out by the WHO 2, Chronic phase CP peripheral blood blasts fewer than 10 in the blood and bone. Accelerated phase AP One or more of the following, Persistent or increasing WBC 10x109 L unresponsive to therapy. Persistent or increasing splenomegaly unresponsive to therapy. Persistent thrombocytosis 1000x109 L unresponsive to therapy. Persistent thrombocytopenia 100x109 L unrelated to therapy. 20 or more basophils in the PB,10 19 blasts in the PB and or BM.
Additional clonal chromosomal abnormalities in Ph cells at diagnosis that include. major route abnormalities second Ph trisomy 8 isochromosome 17q trisomy 19. complex karyotype or abnormalities of 3q26 2, Any new clonal chromosomal abnormality in Ph cells that occurs during therapy. Terminal blast crisis BC phase peripheral blood blasts 20 of peripheral blood. white blood cells or nucleated bone marrow cells extramedullary blast proliferation and. large foci or clusters of blasts on bone marrow biopsy. II Prognosis, The Alberta Provincial Hematology Tumour Team members recommend the use of the Sokal. index and or Hasford score for newly diagnosed patients with CML there is no evidence to. support the use of one method over another The Sokal score was the first scale to calculate. CML risk level 5 A 2009 study demonstrated that the Sokal score was correlated with. cytogenetic and molecular responses in imatinib treated patients 6 For patients receiving IFN. therapy the Hasford prognostic score remains the most reliable prognostic tool 7 Sokal and. Hasford scores can be calculated here, The EUTOS score based on spleen size and percent basophils in peripheral blood can be. used to predict CCyR at 18 months after starting treatment with a TKI 8 The EUTOS score can. be calculated here The Hammersmith prognostic scoring system which has been developed. for patients receiving imatinibfollowing failure with IFN is noteworthy 9 but is not a widely. employed method and has not been validated in patients receiving a front line TKI. The ETLS score is based on an analysis of 2290 patients with chronic phase CML treated with. imatinib in six clinical trials and further validated in an independent sample of 1120 patients In. both sets of patients the ETLS score was better able to predict the probability of dying from. CML compared to Sokal Euro and the European Treatment and Outcome Study EUTOS. score The ETLS score identified 61 of patients as low risk and 12 of patients as high risk. The probability of dying from CML 8 year probability was 7 95 CI 5 10 in the high risk. group 4 95 CI 3 6 in the intermediate risk group and 3 95 CI 2 4 in the low risk. group The study found that higher age more peripheral blasts bigger spleen and low platelet. counts were significantly associated with increased probabilities of dying of CML117 An online. calculator for the ETLS score is available here,Page6 of 32. CLINICAL PRACTICE GUIDELINE LYHE 001, Baseline characteristics such as age spleen size platelet count peripheral blood counts.
basophil count and eosinophil count should be recorded so that alternative scores can be. calculated at a later time, The introduction of imatinib and other TKIs for the treatment of CML has dramatically improved. overall survival among CML patients A recent study of 2 662 patients with CML from Sweden. diagnosed between 1973 and 2013 demonstrated significant improvements in life expectancy. among CML patients over the study period particularly among younger patients Patients. diagnosed in 2013 on average lose 3 life years as a result of their CML diagnosis118 Taken. together imatinib and new TKIs along with allogeneic stem cell transplantation and other factors. have contributed to the life expectancy in patients with CML approaching that of the general. population today,III Diagnosis and Baseline Investigations. The following investigations are recommended at diagnosis for all patients with suspected or. confirmed CML,Bone marrow aspirate and biopsy,Baseline bone marrow cytogenetics. Peripheral blood or bone marrow quantitative real time polymerase chain reaction Q. The bone marrow aspirate and biopsy are helpful in quantifying blasts and other morphological. findings may support a diagnosis of advanced phase CML. The BCR ABL1 gene and its resulting transcripts provide specific markers for the diagnosis and. monitoring of minimal residual disease MRD Methods available to detect the BCR ABL1 gene. include conventional cytogenetics karyotype analysis fluorescence in situ hybridization. FISH and quantitative reverse transcriptase polymerase chain reaction Q RT PCR. Bone marrow karyotype analysis is the only method that allows for the evaluation of all. chromosomes and is recommended at diagnosis to identify the presence of additional. cytogenetic abnormalities Karyotyping is also useful in the context of primary and secondary. resistance to evaluate the possibility of clonal evolution and when a responding patient has. abnormal blood counts Repeat karyotyping should be done at one year and in the setting of not. meeting therapeutic milestones loss of a previous response or newly abnormal blood counts. FISH lacks the sensitivity necessary for monitoring MRD Recent data have shown that the. deletion on the derivative 9 is not prognostic for patients on imatinib 10 Thus FISH is no longer. necessary to document the presence of this deletion. Q RT PCR enables the detection and accurate quantitation of BCR ABL transcript levels and is. now widely used for the detection and quantification of MRD 11 Two kinds of fusion transcripts. resulting from major e14a2 e13a2 and minor e1a2 breakpoints can be distinguished. according to the breakpoint w, ithin the BCR region These transcripts encode the p210 e14a2 e13a2 and p190 e1a2 fusion. proteins the transcripts of which can be detected using Q RT PCR techniques. All patients should have liver function tests lipase glucose urate cholesterol fasting. glucose HgbA1c lipid panel to assess for possible comorbidities and as a baseline for. possible expected complications,Page7 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001.
Ratios and Log Reduction, Due to RNA degradation over time the analysis of an internal control gene is mandatory to. obtain reliable transcript results Several control genes are used in different laboratories e g. BCR ABL1 or G6PDH Results can be reported as the ratio between BCR ABL1 and the. CONTROL GENE or log reduction in level of transcripts from diagnostic values The two. molecular laboratories in Alberta use ABL1 as their control gene To calculate the log reduction. one must have a diagnostic ratio for the patient in question or a calculated laboratory diagnostic. median ratio Either of these could be used as the baseline but using a laboratory median is. strongly recommended this is derived from calculating the median transcript ratio from 30 to 50. patients at diagnosis The log reduction using the median ratio is calculated using Log Baseline. Median Ratio Current Ratio log reduction Patients who achieve at least a 3 log reduction in. BCR ABL1 transcripts within 12 to 18 months after initial treatment are defined as having. achieved a MMR and to have a low probability of disease progression 12 13 Increasing levels of. BCR ABL1 transcripts are predictive of loss of response if levels rise more than 0 5 log over two. serial samples 13 14 At levels below 3 logs increasing transcripts must be confirmed as there is. variability in the assay at low transcript levels,International Scale IS. The International Scale allows transcript levels to be reported as a percentage with 100 being. baseline for newly diagnosed patients and 0 1 being equivalent to a 3 log reduction To. normalize a laboratory ratio a conversion factor is determined so that the baseline ratio. between BCR ABL1 CONTROL GENE is equivalent to 100 14. International Standardization, When obtaining a conversion factor a further level of standardization is recommended by. normalizing results against those from a reference laboratory with values calibrated against the. initial IRIS trial data This last standardization allows laboratories to have a similar way of. reporting results IS and ensures the ratio reported for patients corresponds to data obtained in. clinical trials 14 17 All reporting should be done using international standardization Most. Canadian laboratories including those is Edmonton and Calgary are in the process of. becoming standardized,IV Treatment Options,Chronic phase CML. The Alberta Provincial Hematology Tumour Team members recommend the use of a tyrosine. kinase inhibitor TKI as first line treatment for all newlydiagnosed chronic phase CML patients. The recommended starting doses are,Imatinib 400 mg day.
Nilotinib 300 mg twice daily,Dasatinib 100 mg day, All TKIs should be used with caution in any patient with a history of cardiovascular disease. notably cardiac arrhythmias The choice of the TKI may be guided by an individual patient s. comorbidities and ability to comply with the dosing regimen In addition in patients with high. disease risk and a low EBMT risk score the choice between a TKI and allogeneic SCT should. Page8 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, be discussed However a trial of a first line TKI is recommended as the early response to TKI. treatment can either reinforce or weaken the indication for allogeneic SCT Table 1 presents. comorbidities predicting adverse events during treatment with a second generation TKI. Compliance with TKI therapy is of the utmost importance It has been shown to decrease over. time and impact outcome 18 20 and thus should be assessed diligently at each visit. Table 1 Comorbidities predicting adverse events during treatment with a second generation TKI. adapted from Valent 2011 21,Dasatinib Nilotinib, Predictive factors Pleural pericardial effusion Progressive PAOD. Established risk Cardiac history Pre existing PAOD. factors Arterial hypertension Pre existing PAOD risk factors. Pre existing autoimmune disorder arterial hypertension adiposity. Prior skin rash on dasatinib smoker age hyperlipidemia. Hypercholesterolemia diabetes mellitus, Potential risk Pulmonary disorders Individual risk factors for PAOD. factors Pulmonary hypertension Increase in fasting glucose. Infectious diseases during nilotinib treatment,Viral re activation Pancreatitis.
Immune cell re activation NK cell expansion,Allergic atopic disorders. Imatinib Mesylate The oral TKI inhibitor imatinib mesylate remains a recommended first line. treatment for all newly diagnosed CP CML patients who do not initially choose related donor. allogeneic SCT The utility of imatinib as first line therapy for CML was established by the IRIS. trial a phase III study that randomized 1 106 newly diagnosed CP CML patients to imatinib 400. mg day or IFN plus cytarabine 22 At six year follow up the cumulative best CCyR rate was. 82 63 of patients randomized to imatinib and still on treatment showed CCyR at last. assessment 23 During the sixth year of treatment there were no reports of disease progression. to AP or BC CML The toxicity profile was unchanged The estimated overall survival was 88. CML specific survival was 95 The IRIS study has been further updated now with median 10 9. years of follow up The 10 year overall survival rate is reported at 83 3 in those patients. randomized to the imatinib arm cross overs not included Approximately half of the patients. assigned to the imatinib arm completed study treatment with imatinib and 82 8 had a. complete cytogenetic response Imatinib related adverse events were uncommon and typically. occurred within the first year of treatment119, A higher starting dose of imatinib 600 800 mg day has been proposed based on a. retrospective analysis of the IRIS dataset 24 and the observation that a more rapid treatment. response is associated with a lower risk of progression and better patient outcomes 25 26 In the. Rationale RIGHT trial the proportion of patients receiving initial treatment with imatinib 400 mg. BID that achieved MMR was 48 at six months and 63 at 18 months 27 Superior responses. with a starting dose of imatinib 600 800 mg day were also reported in the TIDEL I trial the. phase III TOPS trial and the GIMEMA CML working party phase II study 28 30 No benefit was. seen with high dose imatinib in a LeukemiaNet study of high Sokal risk patients 31 A meta. analysis of four trials n 1 673 comparing higher dose imatinib 600 mg day with standard. dosing 400 mg day found modest improvements in the rates of CCyR risk ratio RR 1 17 and. MMR RR 1 26 at 12 months but no difference in all cause mortality or disease progression 32. An expert review found that high dose imatinib could induce a sustained response in patients. with cytogenetic failure or acquired resistance but was less effective in patients with a. Page9 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, suboptimal molecular response 33 It has not been determined if the improved rates of CCyR. and MMR will translate to better long term outcomes Adverse events requiring treatment. discontinuation occur more commonly with higher dose imatinib and may adversely affect. adherence to this regimen Current National Comprehensive Cancer Network guidelines. consider high dose front line imatinib to have only a limited role at this time 34 This is therefore. not recommended in Alberta, Nilotinib Nilotinib is a selective TKI that is about 30 fold more potent than imatinib 35 Its. efficacy as a first line therapy in CP CML was demonstrated in the phase III ENESTnd. Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients trial 36 At. 12 months the MMR rate was 44 with nilotinib 300 mg BID 43 with nilotinib 400 mg BID. and 22 with imatinib 400 mg day CCyR rates at 12 months were also higher with the two. nilotinib doses 80 78 compared to imatinib 65 Progression to AP or BC CML was. 1 with nilotinib versus 4 with imatinib At 24 month follow up MMR rates with nilotinib were. 71 and 67 versus 44 with imatinib 37 Rates of progression to AP or BC CML including. clonal evolution were significantly lower with nilotinib compared to imatinib 0 7 and 2 7 vs. 6 8 Additional supportive data on the use of first line nilotinib were obtained in two phase II. studiesv 38 39 In 2011 Health Canada approved nilotinib 300 mg BID as a first line treatment. option for CP CML Retrospective studies 40 43 and a prospective study 44 have found higher. rates of peripheral artery occlusive disease among patients with CML receiving nilotinib. compared to patients receiving imatinib The prospective study included patients currently. enrolled on the ENESTnd trial Of the total cohort n 159 54 patients were on first line. imatinib 33 were on first line nilotinib 33 had previous imatinib exposure and were on second. line nilotinib 25 had previous nilotinib and were on another therapy and 14 were nilotinib nave. patients not receiving imatinib Peripheral artery occlusive disease was reported in 5 patients all. of which were in the first line second line or post nilotinib groups Kim et al 2013 Similarly. retrospective data has indicated that peripheral artery occlusive disease occurs in approximately. 2 1 12 5 of CML patients receiving nilotinib 40 43. Dasatinib Dasatinib is a Src Abl TKI with activity against a range of imatinib resistant. mutations It is about 325 fold more potent than imatinib 45 Efficacy in the first line setting was. demonstrated in the phase III DASISION Dasatinib versus Imatinib Study in Treatment Na ve. CML Patients trial 46 At 12 months the rate of confirmed CCyR was 77 with dasatinib 100. mg day compared to 66 with imatinib 400 mg day MMR rates were 46 versus 28. respectively Rates of progression to AP or BC CML were not significantly different with. dasatinib versus imatinib 2 0 vs 3 5 At 24 months CCyR rates were 86 and 82 with. dasatinib and imatinib respectively 47 MMR rates were significantly higher with dasatinib 64. vs 46 with 17 versus 8 achieving a 4 5 log reduction At three years MMR MR4 and. MR4 5 were significantly better in the dasatinib arm p 0 001 p 0 0064 p 0 001 respectively. however at three years progression free and overall survival were not significantly higher in the. dasatinib arm Jabbour et al 2014 Two phase II trials provide supportive evidence of the. efficacy of dasatinib in the front line setting 48 49 The phase II randomized study NordCML006. n 46 compared first line dasatinib 100mg QD vs imatinib 400mg QD and showed higher. MR 3 0 in the dasatinib group at 3 months 36 vs 8 p 0 02 and 12 months 81 vs 46. p 0 02 but this improvement did not remain significant at 18 months 73 vs 65 p 0 05. Hjorth Hansen et al 2015 A trial of 246 previously untreated chronic phase CML patients. randomizedpatients toreceive dasatinib 100 mg or imatinib 400 mg The percentage of patients. achieving complete cytogenetic response was significantly higher in the dasatinib group 84. compared to the imatinib group 69 p 0 040 Overall progression free and relapse free. survival were higher in the dasatinib arm though not significantly A larger proportion of. Page10 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, dasatinib patients 58 experienced grade 3 4 toxicities compared to the imatinib group 35.
p 0 001 Thrombocytopenia and pleural effusion were more common in the dasatinib arm. whereas edema nausea and muscle pain were more common in theimatinib arm 49. A study which pooled 2705 patients who were enrolled in clinical trials receivinga combined. 5890 patient years of dasatinib exposure found peripheral arterial occlusive disease PAOD. n 1 and PAOD related events n 5 in 0 2 of patients all of which were grade 3 le Coutre. et al 2013 Multiple studiesevaluating second line dasatinib have found high rates of pleural. effusion skin rash and diarrhea in 15 of CML patients and increase in NK cells and. peripheral edema in 4 15 of CML patients Pulmonary hypertension pericardial effusion. viral reactivation and major bleeding were reported in 1 4 of CML patients 50 54 Dasatinib 100. mg day was approved as a first line treatment option for CP CML by Health Canada in 2011. Bosutinib The randomized phase III trial BELA randomly assigned 502 patients to bosutinib. 500mg day or imatinib 400mg day The complete cytogenetic response rate at 12 months. was not significantly different between bosutinib and imatinib p 0 601 primary end point. However the major molecular response at 12 months was higher with bosutinib 41 95 CI. 35 to 47 compared with imatinib 27 95 CI 22 to 33 two sided P 001 Cortes et. al 2012 Time to CCyr and MMR was faster with bosutinib compared to imatinib p 0 001 and. on treatment transformation to accelerated blast phase occurred more frequently on imatinib. 4 compared to bosutinib 2 In this trial 3 CML related deaths occurred in the bosutinib. arm compared with 8 in the imatinib arm Safety profiles were distinct GI and liver related. events were more frequent with bosutinib whereas neutropenia musculoskeletal disorders and. edema were more frequent with imatinib 55 Bosutinib is not currently approved in front line. therapy in Alberta It is however available in instances where Imanitib Nilotinib or Dasatinib are. not appropriate due to intolerance or comorbidities. Treatment of Elderly Patients with CML The introduction of TKIs for the initial treatment of. CML has dramatically improved overall survival of younger CML patients However the utility of. TKIs in the elderly remains somewhat unclear as several retrospective studies have been. unable to demonstrate relative survival benefit while other show dramatic improvements. A study analyzing 5138 patients diagnosed with CML before and after the introduction of TKIs. using the Surveillance Epidemiology and End Results SEER database showed that overall. survival in 65 74 year olds increased from 38 to 51 and 75 84 year olds increased from 19. to 36 56 Another study using the SEER database to identify 423 CML patients showed that. 75 of patients aged 60 79 years and 46 of patients aged 80 years were treated with. imatinib and those who received imatinib survived significantly longer than those who did not. with no differences in race ethnicity socioeconomic status urban rural residence comorbidities. or insurance status between imatinib users and non users 57 Another study again using the. SEER database examining 11 880 CML patients showed 5 year relative survival advantage of. age 75 years CML patients who were treated with TKIs including second generation TKIs. compared to those who did not 58, In contrast a study of 3173 CML patients using a Swedish database failed to show a significant. difference in 5 year relative survival in patients aged 80 years who received imatinib versus. those who did not 59 though use of imatinib in this patient cohort was low 20 Another study. using the SEER database to identify 8329 CML patients failed to show a significant difference in. 5 year relative survival amongst patients aged 65 years who received imatinib versus those. Page11 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, who did not 60 though again the authors note low imatinib use in the patient cohort No. prospective randomized studies have examined TKI use for elderly CML patients and the use. of second generation TKIs in the elderly has not been well studied. In this population it is reasonable to initiate treatment with a tyrosine kinase inhibitor but. consideration can be given to using a lower dose up front or if starting at the standard dose. having a low threshold for dose reductions as long as there is evidence of some degree of. molecular response, Vascular Risk Assessment for Patients on TKI Therapy. All patients on TKI therapy should have a vascular risk assessment done including the presence. of obesity hypertension diabetes hyperlipidemiaand smoking A Framingham risk score should. be calculated link All attempts should be made to mitigate risk factors particularly if a TKI with. a higher incidence of vascular events is to be utilized This includes smoking cessation and. weight loss as necessary as well as regular physical activity achieving a calculated LDL of. 2 0 mmol L a HgB A1C of 6 a BP of 140 90 or 130 80 in diabetic patients and. consideration of antiplatelet therapy 61 62 This may require the involvement of the patient s. family physician an internist or a cardiologist as indicated. Accelerated Phase and Blast Crisis CML, Phase II trials have investigated the efficacy of front line imatinib 400 800 mg day in AP CML 63. and BC CML 67 68 In AP CML the GIMEMA CML Working Party reported a cumulative best. rate of a major cytogenetic response MCyR was 30 with imatinib 600 mg day progression. free survival PFS at 7 year follow up was 36 5 63 In the STI571 0109 phase II trial 24. achieved MCyR with imatinib 400 600 mg day 12 month PFS was 59 64 At 48 months the. estimated overall survival rate was 45 for patients receiving imatinib 600 mg day however. 82 had discontinued treatment primarily due to progression or lack of efficacy 65 A recent. comparison of imatinib and allogeneic SCT in AP CML reported 6 year PFS 80 with both. approaches in low risk patients however SCT was superior to imatinib in intermediate risk 6. year PFS 92 9 vs 55 7 and high risk patients 5 year PFS 100 vs 18 8 66 A phase II. trial of nilotinib 400 mg BID in AP CML with imatinib resistance intolerance reported an MCyR. rate of 32 with 66 maintaining MCyR at two years 41 In the phase II START A trial of. dasatinib 70 mg BID in AP CML the MCyR and CCyR rates were 39 and 32 respectively. 12 month PFS was 66 69, In the phase II GIMEMA trial in BC CML 50 of patients returned to CP CML and 17 had a.
cytogenetic response with imatinib 600 mg day although long term outcomes were not. significantly affected 67 Median survival was 7 months In the STI571 0102 phase II trial 16. had MCyR with imatinib 400 600 mg day median survival was 6 9 months 68 At 48 months. 97 had discontinued imatinib largely due to progression or lack of efficacy 65 Second. generation TKIs have also demonstrated activity in BC CML In a phase III trial of dasatinib 70. mg BID or 140 mg OD 25 28 of BC CML patients achieved MCyR 70 Supportive data were. obtained in a phase II trial 71 Data for nilotinib are more limited although a phase II trial has. reported marrow responses or a return to CP in about one quarter of BC CML patients 72 Thus. TKIs can induce a sustained response and provide a survival advantage over previous. therapies However there is a need for improved treatment approaches for patients in advanced. phases of CML Table 2 presents recommended doses of TKI in AP and BC CML. Table 2 Recommended TKI doses in AP and BC CML,Page12 of 32. CLINICAL PRACTICE GUIDELINE LYHE 001,Imatinib Nilotinib Dasatinib. Accelerated phase 600 mg daily 400 mg BID 70 mg BID. Blast crisis 800 mg daily 70 mg BID,Monitoring Treatment Response. Response assessments should be categorized either as an optimal response or as treatment. failure as summarized in Table 3 this excludes the category of suboptimal response in the. European LeukemiaNet ELN guidelines 73, The recommended definitions of optimal treatment response on TKIs are. First line, BRC ABL1 10 at least 1 log reduction and or Ph 35 at 3 months.
BRC ABL1 1 2 log reduction and or Ph 0 at 6 months. BRC ABL1 0 1 3 log reduction at 12 months and thereafter. Second line in the case of failure of imatinib, BCR ABL1 10 at least 1 log reduction and or Ph 65 at 3 months. BCR ABL1 10 at least 1 log reduction and or Ph 35 at 6 months. BCR ABL1 1 2 log reduction and or Ph 0 at 12 months. BCR ABL1 0 1 3 log reduction thereafter, The recommended definitions of treatment failure on TKIs are. First line,Non CHR and or Ph 95 at 3 months,BCR ABL1 10 and or Ph 35 at 6 months. BCR ABL1 1 and or Ph 0 at 12 months, Thereafter loss of CHR CCyR or confirmed loss of mutations CCA Ph or MMR on two. consecutive tests of which BCR ABL1 transcripts level 1 in at least 1 test. Second line in the case of failure of imatinib,No CHR or Ph 95 at 3 months.
BCR ABL1 10 and or Ph 65 and or new mutations at 6 month. BCR ABL1 10 and or Ph 35 and or new mutations at 12 months. Thereafter loss of CHR CCyR PCyR or new mutations or confirmed loss of CCA Ph or. MMR in 2 consecutive tests of which one with a BCR ABL transcripts level 1. Table 3 Response and failure during first line TKI therapy 73. Time Optimal response Failure Warnings,Diagnosis N A N A High risk or. CCA Ph a major route, 3 months BCR ABL1 10 and or Non CHR and or Ph BCR ABL1 10 and or Ph. Ph 35 95 36 95, 6 months BCR ABL1 1 and or BCR ALB1 10 and or BCR ABL1 1 10 and or. Ph 0 Ph 35 Ph 1 35,Page13 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001. 12 months BCR ABL1 0 1 BCR ABL1 1 and or BCR ABL1 0 1 1. Any time BCR ABL1 0 1 Loss of CHR CCA Ph 7 or 7q,during Loss of CCyR.
treatment Confirmed loss of, CCA Ph is a warning factor at diagnosis Its occurrence during treatment i e clonal progression is a marker of treatment failure. Two consecutive cytogenetic tests are required and must show the same CCA in at least two Ph cells. MMR loss in 2 consecutive tests of which one with a BCR ABL1 transcripts level 1. Recent studies have indicated that a more rapid and deeper molecular response is associated. with a lower risk of treatment failure An analysis of IRIS trial data found poorer event free. survival EFS and progression rates if BCR ABL transcript levels were 10 at 6 months and. 1 at 12 months 7 year EFS was 95 if patients achieved MMR BCR ABL 0 1 by 18. months 74 In the German CML Study IV of imatinib a cut off value of a 1 log reduction 10 in. BCR ABL transcript levels at three months was a highly significant predictor of treatment failure. and disease progression 75 A single centre analysis reported that patients treated with first line. imatinib followed by a second generation TKI with transcript levels 9 84 at 3 months had a. significantly lower 8 year probability of OS 56 9 vs 93 3 compared to those with lower. transcript levels a cutoff of 9 54 at 3 months was predictive of poorer 8 year PFS 57 0 vs. In the DASISION trial a reduction in BCR ABL transcripts to 10 at three months with either. front line dasatinib or imatinib was associated with a greater likelihood of achieving CCyR by 12. months and MMR by 24 months 77 The same 10 cut off value at three months was. predictive of achieving CCyR and MMR at two year follow up in the UK SPIRIT 2 study of front. line dasatinib and imatinib 78, Peripheral blood Q RT PCR should be performed every 3 months If a molecular response. greater than 3 log reduction MMR is reached and stable for 2 years the frequency of Q RT. PCR may be decreased to every 4 6 months Bone marrow karyotyping may be employed as an. alternative to Q RT PCR until CCyR 1 IS is achieved Bone marrow karyotyping should be. considered at 1 year to confirm CCyR and to detect clonal progression or other. abnormalities Thereafter marrow karyotyping does not need to be performed annually unless. there are clonal abnormalities that need to be followed. Monitoring should be consistently performed using the same medium blood or bone marrow. since transcript levels can be different within these compartments even when the sample is. taken at the same time A variation of more than 0 5 log may be seen because of the change in. compartment rather than a change in disease biology. Mutation Testing, Mutation in the ABL1 kinase domain KD is one of several mechanisms of resistance BCR. ABL1 mutations impair imatinib binding to the ATP site to varying degrees Mutations are more. commonly found in the context of secondary resistance but have been documented in about. 30 of early CP CML 78 Primary resistance to imatinib is rare but is more common in advanced. CML 79 More than 90 mutations in the KD of BCR ABL1 have been described and associated. with varying levels of drug resistance Some mutations confer drug resistance and are. Page14 of 32,CLINICAL PRACTICE GUIDELINE LYHE 001, associated with disease relapse Some mutations confer clinical insensitivity to second. generation TKIs, Mutation testing is recommended in imatinib treated patients upon failure to achieve CHR at.
three months at least a 1 log reduction at six months CCyR at 12 months or any sign of loss of. response hematologic relapse relapse to Ph positivity or an increase in BCR ABL transcript. ratios with a 0 5 log 3 2 fold increase in two successive samples and loss of MMR Mutational. analysis should always be performed before switching TKIs. Mutational status and specific mutations may influence therapy after imatinib failure see Table. 4 Patients presenting with F317L V Q252H or V299H mutations have a lower incidence of. favourable response when treated with dasatinib whereas patients with E255K V Y253H or. F359C V respond sub optimally to nilotinib 80 The presence of these specific mutations may. guide the choice of a second generation TKI in imatinib resistant patients Other factors such. as comorbidities tolerability drug availability physician and patient preference should also be. taken into account Table 1presents comorbidities predicting adverse events during treatment.

Related Books

About Brain Injury: A Guide to Brain Anatomy

About Brain Injury A Guide to Brain Anatomy

Pretty much all tissues in the body swell when traumatized. They also require more oxygen to heal. The brain is unique in that it rests inside a bone case, so when it swells, it experiences more trauma. The more damage the brain receives, the more it swells. This is caused by leakage from blood vessels. When

Overview International Health Regulations (IHR)

Overview International Health Regulations IHR

Overview International Health Regulations (IHR) Yitades GEBRE MD Risk Communication Training workshop ... 2014 2016 AW2: Strengthen national disease prevention, surveillance, control and response systems ... 1. marzo 2009. 2. continuo. 3. diciembre 2008 Falta de un programa regular de

An Empirical Study of Indian Classical Ragas Desh and Todi ...

An Empirical Study of Indian Classical Ragas Desh and Todi

An Empirical Study of Indian Classical Ragas Desh and Todi Structure and its Influence on Brain Waves ... Each raag elicits a unique emotional state (rasa) consisting of one or more of these emotions [4]. A. Emotions and Ragas Each raga is uniquely defined by its pitch collection and characteristic phrase. Each raga has some mood associated with it that can be related to its pitches and their ...

Antiviral activity of different misai kucing extracts ...

Antiviral activity of different misai kucing extracts

Misai kucing in Malaysia), kumis kucing in Indonesia and Java tea in Europe (Pujol et al. 2002, Kratz et al. 2008, Xiang et al. 2011). It has been used traditionally to treat various problems including microbial diseases, fever, hepatitis and jaundice (Arthanari et al. 2012). Previous phytochemicals screening studies show that the plant

MUNICIPAL DOCKET MAYOR AND BOARD OF ALDERMEN MEETING ...

MUNICIPAL DOCKET MAYOR AND BOARD OF ALDERMEN MEETING

municipal docket mayor and board of aldermen meeting february 2, 2016 beginning at 6:00 p.m ... services $200.00 690965 public defender 1-19 ...

The Gold Rush of 1849 and the Consequences - Homework

The Gold Rush of 1849 and the Consequences Homework

to mine much deeper below ground to find gold. This meant individuals were very unlikely to strike it lucky after the early 1850s. The Gold Rush of 1849 and the Consequences - Homework The early mining settlements were just camps, they later developed into towns. They were often full of disappointed miners who had failed to make their fortunes. This would have serious consequences for law and ...

A prototype mobile money implementation in Nigeria

A prototype mobile money implementation in Nigeria

operators (William and Suri, 2010). Therefore, the adoption will not lead to any form of social exclusion. Usability is enhanced in the design and the user does not have to memorise commands. DESIGN METHODOLOGY 3-tier architecture was employed. Django and Python were used as the front-end, Apache HTTP was used as the Web server (Middleware) and MySQL was used as the data store (Back-end). The ...

Trigonometry/Pre-Calculus

Trigonometry Pre Calculus

of pre-calculus. In trigonometry students will not only learn the basic trigonometric functions and how to apply them to solve real-life problems, but will explore a number of topics from trigonometry including: triangle properties, radian, identities, solving complex equations, inverse functions, vectors, and the polar coordinate system ...

Year 11 Mathematics: Specialist Course Outline

Year 11 Mathematics Specialist Course Outline

Text: Mathematics Specialist Units 1 and 2 A.J. Sadler . Unit/time Topic/syllabus entry Resources Assessment Week 1 Preliminary work. Week 2 Representing vectors in the plane by directed line segments : 1.2.1 examine examples of vectors, including displacement and velocity 1.2.2 define and use the magnitude and direction of a vector : 1.2.3 represent a scalar multiple of a vector : 1.2.4 use ...

Do you want to work on the - Automated Intelligence

Do you want to work on the Automated Intelligence

complex applications hosted in Microsoft Azure, while being given the trust and freedom to implement the best solutions as you see them. This is a hands-on development role, where you will be deploying new code daily. We are looking for someone who loves to work with others; to guide, educate, and learn from. You must have a natural enthusiasm for solving real problems, and a strong drive to ...