Review Article

316 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 27, NO. 6, 2014 Review Article

Chronic myeloid leukaemia: A paradigm shift in management

ALAKANANDA DASGUPTA, LALIT KUMAR

ABSTRACT EPIDEMIOLOGY In early 2000, a better understanding of the molecular CML has a worldwide annual incidence of 1–2 cases per 100 000 biology of chronic myeloid leukaemia established a central population and this incidence is fairly constant in different role for enhanced tyrosine kinase activity leading to targeted countries. The disease can occur at any age, but the median age at therapy with imatinib mesylate. This paradigm shift in the diagnosis is between the 5th and 6th decades of life with a slight management of this disease has improved the median survival male predominance. In India, from the population-based cancer from 8–9 years before 2000 to an estimated 25 years. registry data (covering 7% of population), an age-adjusted Rapid research in this area along with well-designed incidence of 0.8–2.2 per 100 000 population has been reported. multicentric clinical trials have resulted in the development Though from hospital-based data, CML appears to be a common leukaemia among adults with a median age of 38–40 years at of second- and third-generation tyrosine kinase inhibitors, diagnosis.2,3 The reasons for the younger age at onset are not clear, which are more effective for patients who develop resistance though different population demographics in India (65% of the to imatinib. The synergy of haematological, cytogenetic and population is below 35 years of age) could be a possibility. Other molecular parameters is the mainstay of monitoring patients important differences include diagnosis in the asymptomatic with chronic myelod leukaemia. Early identification of patients stage in <10% of patients (compared with 20%–40%), presence of likely to have suboptimal response to initial tyrosine kinase splenomegaly in >90% of patients (compared with 20%–25%), inhibitors and when to discontinue therapy in those with an presence of hepatomegaly and fever in up to one-third of patients optimal response are areas of active research. and a higher proportion of patients with Sokal poor or high-risk Natl Med J India 2014;27:316–23 score (see below).2–4 GENETICS AND MOLECULAR BIOLOGY INTRODUCTION At diagnosis, 90%–95% of cases of CML have a characteristic Chronic myeloid leukaemia (CML) is a clonal disorder of a translocation, t(9;22)(q34;q11.2) called Philadelphia (Ph) pluripotent stem cell and results from translocation of the ABL chromosome. Molecular techniques have identified the critical gene on chromosome 9 to the region of the BCR gene on genes involved as v-abl (Abelson murine leukaemia viral oncogene chromosome 22 (t[9;22]). This leads to the formation of the homologue [ABL]) on chromosome 9 and breakpoint cluster BCR–ABL fusion gene which encodes an abnormal chimeric region (BCR) on chromosome 22. This translocation fuses protein (BCR–ABL p210) with constitutively activated tyrosine sequences of the BCR gene on chromosome 22 with regions of the kinase activity.1 The latter is responsible for the activation of ABL1 gene from chromosome 9. The remaining cases either have signal transduction pathways leading to abnormal bone marrow variant translocations that involve a third or even fourth proliferation and the clinical and laboratory manifestations of chromosome in addition to chromosome 9 and 22, or may have a CML.1,2 The natural history of untreated CML is bi- or triphasic: cryptic translocation of 9q34 and 22q11.2 precluding identification there is an initial indolent chronic phase (CP) followed by an by routine cytogenetic analysis. In such cases, the BCR–ABL1 accelerated phase (AP), a blast phase or blast crisis (BP or BC) fusion gene is present and can be detected by reverse transcription or both. In CP, the leukaemic cells are minimally invasive and polymerase chain reaction (RT-PCR) or fluorescence in situ the proliferation is largely confined to haematopoietic tissues, hybridization (FISH) analysis.1 The Ph-negative, BCR–ABL- primarily blood, bone marrow and spleen although the liver may positive CML behaves clinically like Ph-positive CML.5 also be infiltrated. In BC, extramedullary tissues, including The site of the breakpoint in the BCR gene may influence the lymph nodes, skin and soft tissues may show infiltration by phenotype of the disease. In CML, the breakpoint almost always is blasts.2 in the major breakpoint cluster region (M-BCR), spanning exons 12–16 (previously known as b1–b5) and an abnormal fusion protein p210 is formed which has enhanced tyrosine kinase activity in Dr B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India excess of the normal 145 kDa ABL product. Rarely, the breakpoint in the BCR gene occurs in the µ-BCR region, spanning exons 17– ALAKANANDA DASGUPTA, LALIT KUMAR Department of Medical 20 (previously known as c1–c4) and encoding a larger fusion Oncology protein, p230. Patients with this fusion may show prominent Correspondence to LALIT KUMAR; [email protected] neutrophilic maturation and/or conspicuous thrombocytosis. Breaks © The National Medical Journal of India 2014 DASGUPTA, KUMAR : CHRONIC MYELOID LEUKAEMIA 317 in the minor breakpoint region, m-BCR (BCR exons 1–2) lead to a The Sokal score shorter fusion protein (p190) and are associated with Ph-positive The Sokal score is based on four factors: (i) patient’s age; (ii) acute lymphoblastic leukaemia (ALL). Very small amounts of the spleen size; (iii) platelet count; and (iv) the percentage of blasts in p190 transcript can be detected in >90% of patients with classical the peripheral blood. The Sokal score is commonly used as a p210 CML as well, due to the alternative splicing of the BCR gene. predictor of response to imatinib.10 p190 may also be seen in rare cases of CML-CP that have increased numbers of monocytes and resemble chronic myelomonocytic Hasford score 1,5–8 leukaemia. The molecular basis of disease transformation is not This was initially described to assess prognosis of patients being well established. Progression is usually associated with clonal treated with interferon. The low-risk group have a score 780, the evolution and, at the time of transformation to AP or BP, 80% of intermediate-risk group have a score >780 and 1480 and high- patients show cytogenetic changes in addition to the Ph chromosome, risk groups have scores >1480.11 such as extra Ph, +8, +19, or i(17q).1,2 European treatment and outcome study (EUTOS) score CLINICAL AND LABORATORY FEATURES The EUTOS score is based on spleen size and basophils. A 2 These have been reviewed earlier. Briefly, 90%–95% of patients EUTOS score >87 indicates that the patient is at a high risk of not are diagnosed in CP which usually has an insidious onset. Nearly achieving a complete cytogenetic response (CCyR) at 18 months.12 20%–40% of patients are asymptomatic and may be detected incidentally on routine white blood cell (WBC) count. The common TREATMENT findings at presentation include fatigue, weight loss, night sweats, Pre-imatinib era splenomegaly and anaemia. Only 5%–10% of patients may be in In the early 20th century, splenic radiation was used till the mid- AP or BC at initial presentation and infrequently, the presentation 1950s when busulphan became available. Busulphan is now used may be akin to acute leukaemia—poor performance status, fever as part of the conditioning regimen for haemopoietic stem cell and symptoms related to severe anaemia, thrombocytopenia or transplantation for acute and chronic leukaemias. It provided marked splenic enlargement.2 effective control of blood counts with reduction in spleen size but Laboratory diagnosis of CML—CP, AP and BC—is generally had no effect on the Ph clone. Bone marrow aplasia (3%), based on the WHO criteria.1 BP or BC may be diagnosed when pulmonary fibrosis and hyperpigmentation were the major adverse (i) blasts >20% of the peripheral blood WBC or the nucleated cells effects.2 of the bone marrow, or (ii) when there is an extramedullary blast Hydroxycarbamide (hydroxyurea) replaced busulphan in the proliferation.2,8,9 Table I lists the investigations to be done at late 1970s. Hydroxyurea is an effective, well-tolerated cyto- different times in the management of CML. reductive agent, and can induce haematological remissions in PROGNOSTIC SCORES most patients, but does not eradicate the leukaemic clone. Interferon-alpha, the first agent to result in any degree of Ph- Three prognostic scores—the Sokal relative risk,10 Hasford relative chromosome negativity in the bone marrow, was introduced in the risk,11 and the EUTOS (European Treatment and Outcome Study) early 1980s and became the treatment of choice for patients not score12 have been developed. These provide useful information eligible for allogeneic stem cell transplantation. Regimens based on for prognostication of CML patients at baseline (Table II). There interferon-alpha induce complete haematological response in up to is no indication if one is better than the other. A high score is 80% of patients and have been shown to extend survival by up to 20 associated with a higher risk of progression to AP or BC. months compared with hydroxyurea. The addition of cytarabine to interferon improved the response and survival, but at the cost of

TABLE I. Investigations at diagnosis and during therapy TABLE II. Prognostic scores At diagnosis Full blood count and differential count Calculation of Sokal score Risk Sokal score10 Hasford score11 EUTOS score12 Bone marrow aspirate with cytogenetic analysis of Formula –Exp [0.0116 –(0.6666 × age (7 × basophils)+ 30 metaphases (age–43.4 years)+ [0 when age <50 years; (4 × spleen size) [FISH for BCR–ABL1 in the absence of a 0.0345 (spleen otherwise 1] + 0.042 where spleen is Philadelphia chromosome] size–7.51) + 0.188 × spleen size (cm below measured in cm qRT-PCR for BCR–ABL1 transcripts to characterize ([platelets/700] costal margin) + 0.0584 below the costal the BCR–ABL1 junction [optional] 2–0.563) + 0.0887 × blasts [%] + 0.0413 margin and Thereafter Blood counts at intervals of 2 or more weeks (blasts–2.1)] × eosinophils [%] + basophils Liver chemistry 0.2039 × basophils as a percentage [0 when basophils <3%; at baseline At 3 months Blood count otherwise 1] + 1.0956 Bone marrow cytogenetics × platelet count [0 when qRT-PCR for BCR-ABL1 transcripts platelets <1500 per µL; At 6 months Blood count–bone marrow cytogenetics otherwise 1]) × 1000 qRT-PCR for BCR-ABL1 transcripts [Thereafter bone marrow aspirates are only required if complete cytogenetic response has not been achieved] Low <0.8 <780 87 At 3-month qRT-PCR for BCR–ABL1 transcripts indefinitely Intermediate 0.8–1.2 780–1480 – intervals thereafter High >1.2 >1480 >87 Source: Modified from reference 9 FISH fluorescent in situ hybridization EUTOS European treatment and outcome study qRT-PCR quantitative reverse transcription polymerase chain reaction 318 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 27, NO. 6, 2014 increased gastrointestinal side-effects and myelosuppression.2,13 A TABLE III. Response criteria* multicentre trial from India evaluated the safety and efficacy of Response European LeukaemiaNet indigenous recombinant interferon-alpha-2b in CML and found the Haematological 14 toxicity profile to be similar to other preparations. Complete Leucocyte count <10×109/L; platelet count <450×109/L; no immature granulocytes; TYROSINE KINASE INHIBITOR (TKI) THERAPY basophils <5%; non-palpable spleen Imatinib mesylate (STI 571, Gleevec, Glivec) was introduced in Cytogenetic 200115 and led to a paradigm shift in the management of CML. Complete No Ph+ metaphases Imatinib is a potent and a specific inhibitor of BCR–ABL1, the Partial 1%–35% Ph+ metaphases tyrosine kinase central to the pathogenesis of CML. Imatinib Major Complete + partial functions through competitive inhibition at the ATP-binding site Minor 36%–65% Ph+ metaphases Minimal 66%–95% Ph+ metaphases of BCR–ABL, leading to the inhibition of tyrosine phosphorylation 16 None >95% Ph+ metaphases of proteins. Molecular In the first prospective, multicentre, open-label, phase 3, Complete Undetectable BCR–ABL by qRT-PCR randomized study (IRIS: International Randomized Study of in two consecutive samples Interferon and STI 571), the combination of recombinant Major Ratio of BCR–ABL to ABL 0.1% interferon-alpha and low-dose cytarabine (n=553) was compared on the International scale with imatinib (n=553).17 In terms of haematological and cytogenetic *modified from references 20 and 21 responses, tolerability and the likelihood of progression to AP or qRT-PCR quantitative reverse transcription polymerase chain reaction BC CML, imatinib was superior to interferon-alpha with low- dose cytarabine as first-line therapy in newly diagnosed CP ABLE 17 T IV. Studies from India on the use of imatinib mesylate for CML. At 8 years of follow-up, patients randomized to the chronic myeloid leukaemia imatinib arm continued to show durable haematological and cytogenetic responses, low progression rates to AP or BC, and Parameter Medhi et al. Rajappa et al. Ganesan et al. Deshmukh et al. excellent survival outcomes.18 This trial established imatinib (2010), (2008), NIMS, (2011), CIA, (2005), TMH, AIIMS, Hyderabad24 Chennai25 Mumbai26 mesylate (400 mg daily) as the first-line therapy for CML. This New Delhi23 study also showed that patients in the imatinib group who had a n reduction in the level of BCR–ABL transcripts of >3-log compared 400 201 516 174 Age (years) with a standardized baseline had a negligible risk of disease Median 35 32 35 38 18 progression over the subsequent 12 months. Fluid retention, Range 7–75 18–72 6–70 4–79 muscle pains and cramps or gastrointestinal disturbances are Gender (%) important adverse effects associated with imatinib.15 Overall, Men 66.3 69.2 66.5 70.1 imatinib is highly effective in 60% of CML patients, poorly Phase (%) tolerated in up to 20% of patients and inadequate to achieve or Chronic 90.7 100 100 55.8 maintain optimal response in a further 20% of patients.19–22 Accelerated 6.5 – – 27 Blast crisis 2.7 – – 17.2 Response criteria Haematological response (%) Complete + 286/400* 97 91.1 72.4 The excellent response following imatinib therapy led to the need partial for response criteria. European LeukaemiaNet (ELN) and NCCN Cytogenetic response (%) (National Comprehensive Cancer Network) have defined response Complete 53 56 23.2 41.7, 27.3 criteria and these are widely used (Table III). Partial 19 23 58 – Major 72 17 81.2 – Experience from India Minor 19 4 – – Many studies from India have found the toxicity profile of No response 9––– imatinib to be similar to that reported elsewhere in the world * at last follow-up  early and late chronic phase AIIMS All India Institute of (Table IV).23–26 Medical Sciences NIMS Nizam’s Institute of Medical Sciences CIA Cancer Institute, Adyar, Chennai TMH Tata Memorial Hospital, Mumbai MONITORING THE RESPONSE

Routine cytogenetic analysis is still considered the gold standard TABLE V. Time-points for responses to tyrosine kinase inhibitors for evaluating response in CML (Table I).21,27 It has been assumed (imatinib) that increased accuracy might be better at predicting outcome. A Time (months) Optimal response Suboptimal response Failure single measurement of BCR–ABL1 transcripts performed at 3 3 CHR

IMATINIB RESISTANCE selecting an initial TKI, but becomes relevant in patients who Primary haematological resistance (defined as failure to obtain a relapse.40 CHR at 3 months, Table V) occurs in about 5% of patients. About 15% of patients have primary cytogenetic resistance (defined as SECOND-GENERATION TKIS failure to achieve either a major cytogenetic response (<35% Ph- The understanding of the mechanism of resistance to imatinib led positive marrow metaphases) after 6 months of therapy, or a to the rapid development of new drugs to circumvent resistance.49 CCyR after 12 months of therapy). Secondary or ‘acquired’ haematological and cytogenetic resistance refers to loss of a Dasatinib previously established response.29 Dasatinib (Table VI) is structurally unrelated to imatinib and is Development of resistance to imatinib mesylate in patients approximately 325-fold more potent than imatinib.50 In a randomized with CML is often accompanied by selection of point mutations study, dasatinib (100 mg daily, n=259) was compared with imatinib in the kinase domain (KD) of the BCR–ABL oncoprotein, where (400 mg daily, n=260) in treatment-naive CML-CP patients. Patients imatinib binds.38 To date, more than 70 different BCR–ABL KD in the dasatinib arm had higher rates of CCyR (83% v. 72%) and mutations, encoding for over 50 different amino acid substitutions, major molecular response (46% v. 28%) at 12 months, and an have been described.39,40 Nilotinib and dasatinib (second-generation acceptable safety and tolerability profile.51 In a 2-year follow-up of TKI) are active against the majority of imatinib-resistant mutations, this study, first-line dasatinib resulted in faster and deeper cytogenetic but some confer clinical resistance to nilotinib (Y253H, E255K, and molecular responses compared with imatinib. This led to better E255V, F359V and F359C), dasatinib (V299L, T315A, 2-year PFS and overall survival.52 Studies have shown the benefit F317L,F317I, F317V and F317C) or both (T315I). Other mutations of dasatinib 70 mg twice daily in patients with AP CML, who are have decreased in vitro sensitivity to dasatinib, such as E255K and intolerant or resistant to imatinib. Once-daily treatment was E255V.41 The BCR–ABL T315I mutation is resistant to imatinib, associated with an improved safety profile.53 nilotinib and dasatinib in CML.42–45 For such patients the available options are ponatinib, omacetaxine and allogeneic stem cell Nilotinib transplant.45 Akin to imatinib, nilotinib functions through competitive inhibition Studies from India have identified BCR–ABL mutations in at the ATP-binding site of BCR–ABL, leading to the inhibition of 45%–50% of patients who are resistant to imatinib. These mutations tyrosine phosphorylation of proteins. Nilotinib (300 mg twice a may be higher in patients with more advanced disease. Sharma et day and 400 mg twice a day) was compared with imatinib in a al. found point mutations to be the major mechanism for primary phase 3, randomized, open-label, multicentre study, in newly cytogenetic resistance.46 Patients with mutations had inferior diagnosed patients with CP CML.54 At 12 months, the major progression-free survival (PFS) compared to those without molecular response rate was 44% for the 300 mg dose and 43% for mutations.46 Similar results have been reported in a study from the 400 mg dose compared to 22% for the imatinib arm. The rates southern India.47 A study by Kagita et al. reported 15 exonic of CCyR at 12 months were higher for nilotinib (80% for 300 mg mutations in 46% of patients; among them, 7 patients had multiple dose and 78% for 400 mg dose) compared with 65% for imatinib.55 mutations.48 The KD mutation profile plays little, if any, role in Although dasatinib has been shown to be 16-fold more potent 320 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 27, NO. 6, 2014 than nilotinib at inhibiting unmutated BCR–ABL in vitro, no therapy indefinitely in all patients who respond to treatment, even direct comparisons between these agents in patients with CML those with undetectable minimal residual disease (MRD).21,27 have been reported. Major molecular response (i.e. a 3-log reduction in BCR–ABL1 transcript levels, BCR–ABL ratio 0.1%) is used in current treatment Bosutinib guidelines to assess prognosis. Deeper molecular responses MR4, Bosutinib (SKI-606) is an oral, dual SRC/ABL TKI with clinical correspond to a BCR–ABL ratio <0.01%, MR4.5, to a ratio activity in Ph-positive leukaemia.56 A phase 3 trial compared the <0.0032% and undetectable molecular disease, correspond to 5- efficacy and safety of bosutinib in newly diagnosed patients of log reduction or <0.001%.31,64,65 CML. A total of 502 patients were randomized to receive bosutinib 500 mg per day or imatinib 400 mg per day.The CCyR TREATMENT-FREE REMISSION rate at 12 months was similar—bosutinib (70%) versus imatinib This has recently emerged as a new goal of treatment in CML. (68%). The major molecular response rate at 12 months was Molecular remission is sustained in around 30% of imatinib- higher with bosutinib (41%) compared with imatinib (27%). treated patients who stop treatment after 2 years with Time to CCyR and major molecular response was faster with undetectable molecular disease by conventional RT-PCR bosutinib.57 method.66–69 An additional 20%–30% of patients will lose undetectable molecular disease, but remain in stable major THIRD-GENERATION TKIS molecular remission off treatment. Results from a German study Ponatinib indicate that patients in deep remissions (MR >4.5) have more Ponatinib (AP24534), a novel TKI agent is a pan-BCR–ABL stable remissions with lower probabilities of progression, and inhibitor with substantial and durable clinical activity in patients may be considered for discontinuation of therapy.66 Recent with Ph-positive leukaemias with resistance to TKI. Ponatinib evidence suggests that deeper molecular responses (4-log blocks native and mutated BCR–ABL, including the gatekeeper reductions in BCR–ABL1 transcript levels), particularly when mutant T315I, which is uniformly resistant to TKI.58 Studies attained early during treatment, may have even better event-free, suggest that a high proportion of patients resistant to two or more progression-free and overall survival and a low risk of progression TKIs achieve excellent response. The common adverse events are and disease relapse and also seem less likely to lose major rash, myelosuppression and constitutional symptoms.59 molecular response. Factors associated with a higher probability of treatment-free remission include low-risk Sokal score, prior Homoharringtonine/omacetaxine mepesuccinate interferon treatment, longer total duration of imatinib treatment Omacetaxine mepesuccinate is a reversible protein translation and higher number of natural killer cells at the time of inhibitor. The drug is derived from the bark of species of the discontinuation of imatinib.67 Independent predictors of stable, Chinese plum yew, cephalotaxus. The drug is not dependent on undetectable BCR–ABL1 during first-line imatinib therapy were BCR–ABL binding for its activity; instead it binds to the A-site female sex and <10% BCR–ABL1 transcripts at 3 months.68 cleft of ribosomes, resulting in a profound but transient inhibition Studies by the French CML Intergroup (STIM-stop imatinib) in of protein synthesis.60 Currently, the drug is approved for treatment 100 patients indicate that imatinib can be safely discontinued in of patients with CP or AP CML whose disease has progressed patients with a complete molecular remission of at least 2 years’ during treatment with at least two TKIs. The adverse effects are: duration.69 Similar results have been reported by the Australasian grade 3/4 haematological toxicity included thrombocytopenia Leukaemia and Lymphoma Group.70 The most recent study from (54%), neutropenia (48%) and anaemia (33%). Non- the French CML Intergroup, STIM2, enrolled 124 imatinib-only haematological adverse events are predominantly grade 1/2 and patients between April 2011 and June 2013. Using the original include diarrhoea (44%), nausea (30%), fatigue (24%), pyrexia definition of molecular recurrence, 61% of patients were in (20%), headache (20%) and asthenia (20%).61,62 treatment-free remission at the time of the interim analysis (median follow-up 12 months).71 The studies outlined above MOLECULAR MONITORING OF CML have generally included patients in CP only, with no history of Serial analysis of BCR–ABL mRNA levels by qRT-PCR is the BCR–ABL1 kinase domain mutations.71 Thus, achieving a most sensitive tool for monitoring. qRT-PCR can reliably detect sustained deep molecular response is a requirement for residual disease to a sensitivity of 0.01% and often to 0.001%. The consideration of discontinuation of therapy.65,72 present method uses specific primers to detect transcripts arising from BCR–ABL1 and compares these with the numbers of ALLOGENEIC STEM CELL TRANSPLANT: CURRENT transcripts from a control gene (typically BCR, ABL1, and beta- INDICATIONS glucuronidase [GUSB]); ABL is currently the most widely used Following introduction of imatinib, the number of patients control gene. The results are expressed as a ratio of BCR–ABL1 undergoing allogeneic stem cell transplants has reduced transcripts to the control transcripts, multiplied by 100 to give the considerably.73 The present indications for transplant include result as a percentage, where 10%, 1%, 0.1%, 0.01% and 0.001% patients in AP or BC, patients with T315I mutation and patients correspond to a reduction in tumour load of 1, 2, 3, 4 and 5 logs. after failure or intolerance of second-generation TKI, and children Peripheral blood is suitable for analysis of BCR–ABL transcripts. with CML who fail to achieve major cytogenetic response or a A minimum of 5 ml (preferably 10 ml) should be collected. EDTA BCR–ABL transcripts level <10% at 6 months despite receiving anticoagulant is appropriate for PCR analysis. To prevent second-generation TKIs.19,73 The decision involves careful significant degradation of transcripts, samples should be processed balancing of the risks for transplantation against the risks of within 36 hours of collection (ideally within 24 hours).63,64 disease progression in each patient.74

DURATION OF THERAPY PREGNANCY Current guidelines such as ELN recommend continuing TKI The treatment of CML during pregnancy remains a clinical DASGUPTA, KUMAR : CHRONIC MYELOID LEUKAEMIA 321

TABLE VII. Annual price estimates, by region, of drugs approved nilotinib and dasatinib. The choice should be based upon the for the treatment of chronic myeloid leukaemia availability, risk profile of CML, long-term goals and patient’s Country Price in thousands of US$ comorbid conditions.19 The availability of second- and third-line (rounded to nearest $0.5 thousand) TKIs has expanded the treatment options. Regular monitoring of Imatinib Nilotinib Dasatinib BCR–ABL transcript has helped to identify poor responders and USA 92 115.5 123.5 consider changes in therapy. The additon of low-dose interferon- Germany 54 60 90 alpha or pegylated interferon along with imatinib has resulted in United Kingdom 33.5 33.5 48.5 a deeper molecular response.81 Excellent response and improved Canada 46.5 48 62.5 survival following TKI therapy has led to ‘treatment-free remission’ Norway 50.5 61 82.5 as a new goal. 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