Chronic myeloid leukaemia

Seminar

Chronic myeloid leukaemia Jane F Apperley

In less than 10 years, the prognosis of chronic myeloid leukaemia has changed from that of a fatal disease to a disorder amenable simply to lifelong oral medication and compatible with a normal lifespan. This change has been made possible by a deep understanding of the molecular pathogenesis and a determination to develop targeted and selective drugs. This Seminar summarises the presentation, pathophysiology, diagnosis and monitoring technology, treatment options, side-effects, and outcomes of chronic myeloid leukaemia, and discusses the possibility of cure—ie, stable undetectable or low level disease in the absence of medication. Chronic myeloid leukaemia continues to instruct us in the mechanisms of leukaemogenesis and provides hope not only for similar developments in management of other malignancies, but also for the remarkable speed with which these can move from bench to bedside.

Epidemiology Chronic myeloid leukaemia affects about one individual per 100 000 population per year with a slight male preponderance, and accounts for 15% of all new cases of leukaemia in the Western hemisphere. Before the development of targeted therapy with tyrosine kinase inhibitors (TKIs), the median survival was 5–7 years. TKIs have profoundly affected outcome and hence prevalence: present predictions suggest that in the USA prevalence will rise from 70 000 cases in 2010, through 112 000 in 2020 to a plateau of 181 000 in 2050.1

Pathophysiology Chronic myeloid leukaemia is a clonal haemopoietic stem cell disorder characterised by a reciprocal translocation between the long arms of chromosomes 9 (ch9) and 22 (ch22). The abnormal ch22 was first observed in Philadelphia, USA—hence the common terminology, Philadelphia (Ph) chromosome—but the reciprocal translocation of ch9 was not recognised until 1973.2 t(9;22) results in the juxtaposition of the human analogue of the v-ABL oncogene from ch9 with the BCR housekeeping gene on ch22 to produce the fusion BCR-ABL1 gene. This fusion gene is transcribed into BCR-ABL1 mRNA, and translated into the Bcr-Abl1 protein (figure A). The identification of the fusion gene was facilitated by the close proximity (5 kb) of the breakpoints on ch22, hence the term breakpoint cluster region (BCR). Sequencing of the BCR showed five exons (b1–b5), with the most frequent breakpoints being between b2 and b3 or b3 and b4 (figure B). The breakpoints within the ABL1 gene on ch9 were distributed along a much wider region, but always resulted in fusion upstream of the second ABL1 exon, so the fusions were originally known as b2a2 or b3a2. Later, b1–b5 exons were shown to be exons 12–16 of a much larger gene, also named BCR, and b2a2 and b3a2 became e13a2 and e14a2. ABL1 encodes a non-receptor tyrosine kinase that phosphorylates substrate proteins via its SH1 domain, and affects crucial cellular activities, such as increased proliferation, loss of stromal adhesion, and resistance to apoptosis.3 Through the loss of upstream control elements in the creation of the fusion gene, Bcr-Abl1 is capable of autophosphorylation and uncontrolled signalling to a

plethora of downstream proteins, activating these effector pathways. A BCR-ABL1 fusion gene is present in all cases of chronic myeloid leukaemia and results in two critical events in the disease. First, the gene provides a unique biomarker for diagnosis and monitoring response to treatment, and second, the fusion tyrosine kinase is susceptible to drug targeting. TKIs block the ATP binding pocket of Abl1 kinase domain, inhibiting phosphorylation, and resulting in cell death.

Published Online December 5, 2014 http://dx.doi.org/10.1016/ S0140-6736(13)62120-0 Department of Haematology, Imperial College London, London, UK (Prof J F Apperley FRCPath) Correspondence to: Prof Jane F Apperley, Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [email protected]

Diagnosis Chronic myeloid leukaemia is triphasic: most patients present in the chronic phase in which symptoms can be fairly easily controlled, but without effective medical intervention will progress through a period of increasing instability known as acceleration, to terminal transformation to an acute leukaemic-like illness or so-called blast crisis. One of the strongest pieces of evidence of the stem cell origin of chronic myeloid leukaemia is that the final transformation phase can result in both lymphoblastic (25%) and myeloblastic (50%) subtypes with a further 25% manifesting biphenotypic or undifferentiated phenotypes. Typically, patients present in chronic phase with one or more of the symptoms and signs shown in panel 1, but with expansion of routine health screening, such patients are being identified increasingly by the chance finding of an elevated white cell count.4 The characteristic clinical finding is splenomegaly. Panel 2 shows diagnostic tests for chronic myeloid leukaemia. Conventional cytogenetics occasionally fails for technical reasons in which case the BCR-ABL1 fusion gene can be identified by fluorescent-insitu-hybridisation (FISH) using specific chromosome markers. In a small proportion of cases, the BCR-ABL1

Search strategy and selection criteria Data for this Seminar were identified by searches of PubMed, Web of Science, abstracts submitted to the American Society of Haematology and the European Haematology Association, and references from relevant articles with the search terms ‘‘chronic myeloid leuk(a)emia’’, ‘‘tyrosine kinase inhibitors’’, ‘‘imatinib’’, ‘‘dasatinib’’, ‘‘nilotinib’’, ‘‘bosutinib’’, and ‘‘ponatinib’’. Only articles published in English between January, 1968, and January, 2013, were included.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

1

Seminar

fusion gene can be present without t(9;22) being detectable by conventional cytogenetics: this situation can be identified by FISH, reverse transcriptase PCR (RT-PCR), or both. This extensive investigation not only confirms the diagnosis, but also allows disease staging and prognostic A

t(9;22)(q34;q11)

scoring. The definitions of acceleration and blast crisis are largely dependent on the proportion of blasts in the blood and bone marrow, but vary in the two commonly used systems (WHO5 and European Leukaemia Net;6 table 1). Direct comparison of studies with the differing criteria is difficult and is further compounded in the field of transplantation by their use of yet another definition set.7 However, most of the recent TKI studies have adopted the European Leukaemia Net criteria. Within the chronic phase, these parameters together with age and spleen size are used in scoring systems for the prediction of survival (table 2).8–10 The Sokal score was developed for patients treated with busulfan, and the Hasford score for patients treated with interferon α, and both continue to have value in the TKI era. The most recent EUTOS score,

Ph

Panel 1: Presenting symptoms and signs of chronic myeloid leukaemia Frequent • Fatigue • Night sweats • Malaise and weight loss • Left upper quadrant pain, discomfort, satiety • Splenomegaly

9q+

B

BCR-ABL1 mRNA

b2a2 b3a2

C

Actin bind.

DNA bind.

NLS

SH3 SH2

rho-GEF

P-S/T (SH2-bind.)

Oligom. domain

p210

SH1

Y412

Bcr-ABl1 protein

*Should raise suspicions of presentation with advanced phase disease.

Panel 2: Mandatory diagnostic tests for chronic myeloid leukaemia

D Bcr-Abl1 protein Imatinib in situ

Figure: Pathogenesis of chronic myeloid leukaemia The t(9;22) reciprocal translocation (A) results in the creation of the BCR-ABL1 fusion gene, which is in turn transcribed to a BCR-ABL1 mRNA (B), and translated to the Bcr-Abl protein (C). Schematic of protein with imatinib in ATP binding loop (D).

2

Less frequent • Priapism • Retinal haemorrhages • Thrombosis, bleeding, or both • Bone pain* • Hepatomegaly • Lymphadenopathy* • Skin infiltration* • Extramedullary mass (chloroma)*

• Blood count with blood film differential. This will typically show a so-called left shift of the myeloid series with the presence of immature myelocytes and metamyelocytes, basophils, and eosinophils. These must be accurately quantified as the results contribute to accurate identification of disease stage and prognostic scoring systems. • Bone marrow aspirate with differential to include percentages of blasts, promyelocytes, myelocytes, esoinophils, and basophils. • Cytogenetics and karyotyping by G banding: fluorescent in-situ hybridisation is not sufficient at diagnosis as it is unable to identify chromosomal abnormalities in addition to the t(9;22) translocation • Reverse transcriptase PCR for BCR-ABL1 mRNA transcripts.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

Seminar

derived from patients given TKIs, is simpler and has been shown to be of value in at least one large study.11

Treatment options Historical The first treatment of chronic myeloid leukaemia occurred in the 19th Century with use of arsenic containing compounds.12 In the early 20th century, splenic irradiation reduced the degree of splenomegaly but was replaced in the 1960s by the alkylating agents, after the first ever randomised study of chronic myeloid leukaemia, which showed improved survival in patients given busulfan.13 Later, there was recognition that busulfan did not always normalise the blood count, and, more importantly, that it might be mutagenic and induce blast crisis, so it was replaced by the ribonucleotide reductase inhibitor, hydroxycarbamide. Busulfan and hydroxycarbamide improved the blood count and gave symptomatic relief, but they did not delay the onset of disease progression, which occurred at a median of 4–5 years after diagnosis. Cytogenetics showed that patients remained 100% Ph positive. In the 1970s, two entirely different treatment strategies— namely, interferon α and allogeneic stem cell transplantation—showed not only the achievement of Ph negativity, but also, and most importantly, that this was associated with prolonged survival.14 Interferon α induced some level of Ph negativity in a significant proportion and complete cytogenetic remission in about 10–15% of patients.15 Subsequently, several randomised clinical trials compared interferon α with busulfan, hydroxycarbamide, or both, and showed that interferon α improved median life expectancy to 6–7 years.16–18 Interferon α is given subcutaneously and is accompanied by a range of side-effects that interfere with quality of life, and for many individuals long-term use was impossible. The addition of subcutaneous cytarabine to interferon α increased the proportion of patients achieving complete cytogenetic remission, and one study showed that this addition had a survival advantage compared with interferon α alone,19 but was associated with increased toxicity. The mechanism of action of interferon α is poorly understood but the drug at least in part reflects a degree of immunomodulation, an approach that is now regaining popularity to try to optimise responses to TKIs.

Allogeneic stem cell transplantation Allogeneic stem cell transplantation for chronic myeloid leukaemia was first described in the context of syngeneic donors20 and later in sibling21 and volunteer unrelated donors.22 Preparative regimens myeloablation with total body irradiation or busulphan, followed by infusion of normal donor stem cells induce durable complete cytogenetic remission in most patients. Allogeneic stem cell transplantation resulted in longterm survival and probable cure, particularly if

WHO criteria5

European Leukaemia Net criteria6

10–19%

15–29% or blasts plus promyelocytes in peripheral blood or bone marrow >30% with blasts <30%

Accelerated phase Blasts in peripheral blood or bone marrow

Basophils in peripheral blood

≥20%

≥20%

Platelets

<100 × 109/L not attributable to treatment, or platelets >1000 × 109/L uncontrolled on treatment

<100 × 109/L not attributable to treatment

Additional chromosomal abnormalities

Occurring on treatment

Occurring on treatment

White cell count and spleen size

Increasing and uncontrolled on treatment

..

Blasts in peripheral blood or bone marrow

≥20%

≥30%

Blast proliferation

Extramedullary, except spleen

Extramedullary, except spleen

Large foci of blasts

Bone marrow or spleen

..

Blast crisis

Table 1: Definitions of accelerated phase and blast crisis according to present classification systems

Sokal8*

Hasford9*

EUTOS10 †

Age (years)

0·116 × (age 43·4 years)

0·666 when >50 years

..

Spleen (cm below costal margin)

0·0345 × (spleen size – 7·51)

0·042 × spleen size

..

Platelets x 10⁹/L

0·188 × [(plts – 700)² – 0·563]

1·0956 when >1500

..

Peripheral blood basophils %

Not included

0·20399 when >3%

7×% 4 × spleen

Peripheral blood eosinophils %

Not included

0·0413×%

Low risk

<0·8

≤780

≤87

Intermediate risk

0·8–1·2

781–1480

..

High risk

>1·2

>1480

>87

*Calculations for Sokal and Hasford done with the European LeukemiaNet risk calculator. †Calculations for EUTOS done at European LeukemiaNet.

Table 2: Scoring systems validated for parameters at diagnosis for treatment with busulfan (Sokal), interferon α (Hasford), and imatinib (EUTOS)

the transplant was performed in chronic phase.23 Unfortunately, the associated transplant-related mortality restricted transplant to younger patients and those with fully HLA-matched donors. In the 1980s, removal of donor T lymphocytes from the transplant product before infusion reduced the incidence and severity of the alloimmune-mediated graft versus host disease. Although highly successful in the short term, this approach increased the risk of relapse,24 which is direct evidence of the long-suspected graft versus leukaemia effect. This observation had far ranging consequences, the most obvious of which was to use infusions of small numbers of lymphocytes from the original donor (donor lymphocyte infusions) to restore durable remissions.25 The risk of further graft versus host disease was largely abrogated by the sequential use of graduated doses of donor lymphocyte infusions.26,27 The knowledge that early relapse after transplant was amenable to donor lymphocyte infusions led logically

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

For the European LeukemiaNet risk calculator see http://www. leukemia-net.org/content/ leukemias/cml/cml_score/index_ eng.html For the European LeukemiaNet see http://www.leukemia-net. org/content/leukemias/cml/ eutos_score/index_eng.html

3

Seminar

to the introduction of post-transplant monitoring by cytogenetic and RT-PCR analyses. The more fundamental effect was the realisation that the cure induced by transplant was not only due to the use of high dose chemoradiotherapy, but also to the ongoing surveillance and destruction of residual leukaemic cells by the donor derived immune system. Reduced intensity conditioning regimens offer reduced toxicity and widen the range of patients, with respect to age and comorbidities, who might benefit from allogeneic stem cell transplantation.28,29 By the 1990s, allogeneic stem cell transplantation was first line treatment for all eligible patients in first chronic phase and early acceleration phase. Intravenous combination chemotherapy, normally reserved for the treatment of acute leukaemia, was used to induce a second chronic phase before transplant in patients with blast crisis. With data submitted to the comprehensive registry of the European Group for Blood and Marrow Transplantation, Gratwohl and colleagues30 developed a risk score for the outcome of myeloablative transplant for chronic myeloid leukaemia based on the parameters listed in table 3. Patients with low Gratwohl scores (0–1) can expect overall survival at 3 years in excess of 90%.31 Since the advent of TKIs, the numbers of transplants done for chronic myeloid leukaemia have greatly declined: one of the major barriers to early transplant had been the fear of transplant related mortality and a trial of an oral targeted drug seemed much preferable to allografting. For most patients, this trust in TKIs was justified and allogeneic stem cell transplantation became Score* Age (years) <20

0

20–40

1

>40

2

Disease phase Chronic phase

0

Acceleration, second of subsequent chronic phase

1

Blast crisis

2

Stem cell source HLA-matched sibling

0

Volunteer unrelated donor or mismatched family member

1

Donor-recipient sex combinations Male to male

0

Male to female

0

Female to female

0

Female to male

1

Time from diagnosis to transplant <12 months

0

>12 months

1

Taken from Gratwohl/European Group for Blood and Marrow Transplantation score.30 *Total score will be in the range 0–7.

Table 3: Factors affecting transplant outcome in chronic myeloid leukaemia

4

second line, then subsequently third or fourth line therapy, restricted to patients who had failed multiple TKIs, or whose disease had progressed. Recent data of regular molecular monitoring suggest that patients destined to fail TKIs can be recognised early, and this information might return allogeneic stem cell transplantation to an earlier timepoint in the disease course.

Tyrosine kinase inhibitors In 1996, Druker and colleagues32 reported the first in-vitro data for the effect of the highly selective 2-phenylaminopyrimidine Abl1 TKI, then known as signal transduction inhibitor 571 (STI571), on chronic myeloid leukaemia cell lines. In a phase 1 study in advanced phase disease, STI571, now known as imatinib, not only controlled blood counts and restored chronic phase, but also induced cytogenetic responses in a substantial proportion of patients.33 A phase 2 study showed a high rate of complete cytogenetic remission in patients in chronic phase who had previously failed (absence of efficacy, intolerance, or both) interferon α.34 Within 2 years of the phase 1 study, the IRIS study (international randomised study of interferon and cytarabine versus STI571) was completed in 1100 newly diagnosed patients, the results of which revolutionised the management of chronic myeloid leukaemia.35 Imatinib was rapidly followed by the second generation drugs, dasatinib, nilotinib and, bosutinib, and most recently the third generation drug, ponatinib. TKIs are oral and administered daily and induce their maximum effect gradually. Tumour load decreases with time and should be monitored regularly. It is worth pausing in the story of TKI development to explain the potential, but also the limitations of present monitoring methodology.

Defining and monitoring responses to treatment The first goal of treatment is normalisation of the blood count, ie—complete haematological remission. If, however, treatment is stopped at this point the blood count rapidly becomes abnormal so it is clear that the total tumour load has not been greatly affected. The second goal is therefore to deepen the response by achieving Ph negativity or complete cytogenetic remission. Conventional cytogenetic examination requires cells to be in mitosis and is technically challenging and laborious. At the time of complete haematological remission, this is not easily achieved with blood and requires a sample derived from an invasive bone marrow aspirate. Even then it is difficult to visualise more than 20 metaphases. If none contain the Ph chromosome, the disease is said to be absent to a level of one in 20 (sensitivity 5%). The sensitivity of chromosome analyses can be enhanced to one per 1000 normal cells (sensitivity 0·1%) by FISH, which can be used in both interphase and metaphase nuclei.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

Seminar

RT-PCR for BCR-ABL1 transcripts was initially developed to detect early relapse after allogeneic stemcell transplantation. Early assays were qualitative—ie, leukaemic cells were present or not—but further developments initially with a competitive PCR in which amplification of BCR-ABL1 fusion transcripts from a patient sample was compared with amplification of a known quantity of a competitor transcript,36 and later with commercial PCR equipment, permitted quantification of residual disease. Modern quantitative RT-PCR (RQ-PCR) can reliably detect residual disease to a sensitivity of 0·01% and often to 0·001%. The present method uses specific primers to detect transcripts arising from BCR-ABL1 and compares these with the numbers of transcripts from a control gene (typically BCR, ABL1, and GUSB). The results are expressed as a ratio of BCRABL1 transcripts to the control transcripts, multiplied by 100 to give the result as a percentage, where 10%, 1%, 0·1%, 0·01%, and 0·001% correspond to a reduction in tumour load of 1, 2, 3, 4, and 5 logs.37 RQ-PCR is now the accepted method for monitoring response to TKIs. Unfortunately, interlaboratory results cannot be compared easily as the equipment, reagents, control genes, and techniques differ between laboratories. The international RQ-PCR standardisation project began in 2006 with the aim of using a common reference baseline to develop a standardised scale.38 The original baseline material was derived from a pool of 30 newly diagnosed patients, tested in three laboratories with a median result identified for each. This median was then used to derive a laboratory specific conversion factor to standardise the results.39 Other laboratories were invited to participate but subsequently the baseline material was exhausted and now conversion factors are created by a comparison of local results with those of the reference laboratory in Adelaide, Australia.40 At present, about 200 laboratories worldwide report their results on the international scale, but many more do not. Efforts continue to create internationally accepted reference material to allow more general uptake of the scheme.41 In 2006, a group of chronic myeloid leukaemia experts came together through the European Leukemia Net, a European Union funded Network of Excellence, to develop recommendations for disease management.6 They advised both cytogenetics and RQ-PCR for monitoring and determined the goals of treatment as complete haematological remission by 3 months and complete cytogenetic remission by 18 months. Updated recommendations in 200942 formally defined a optimal responder as a patient who achieved complete haematological remission by 3 months, complete cytogenetic remission (equivalent to a 2 log reduction in tumour load) by 12 months, and a 3 log reduction (RQ-PCR <0·1% known as major molecular remission or MR³), by 18 months. The guidelines have since been revised in 2013.

Further development of TKIs At a median follow-up of 18 months within the IRIS study,35 complete cytogenetic remission occurred in 76% of patients randomly assigned to receive imatinib and 15% of patients in the interferon α/cytarabine group. Estimated MR³ rates at 12 months were 40% for imatinib and 2% for interferon α/cytarabine. The benefit was so clearly in favour of imatinib that 89% of the patients randomly assigned to interferon α/ cytarabine discontinued their initial treatment with either crossover to imatinib or withdrawal of consent and transfer to commercially available drugs. Follow-up at 8 years showed event free survival and freedom from progression in patients given imatinib were 81% and 92%, respectively.43 These results were validated by independent single centre studies of consecutive patients treated with imatinib.44,45 They also caused difficulties in the design of future studies because the survival of patients treated from diagnosis with imatinib was so prolonged that the most robust endpoint—ie, overall survival, became unrealistic within a reasonable timeframe. As a result, the achievement of surrogate markers of survival—namely, complete cytogenetic remission and MR³—became the endpoints of future trials. MR³ became the main objective of treatment when a later analysis from the IRIS study39 showed that patients who achieved MR³ were highly unlikely to experience disease progression in the next 12 months. However, until recently, it has been difficult to show a benefit in overall surivial for patients achieving MR³ in those achieving complete cytogenetic remission without MR³. Long-term follow-up has since shown that the attainment of progressively deeper molecular responses over time is associated with an excellent rate of freedom from progression compared with those with less deep responses at the same timepoints.46 Very recently several studies have specifically suggested a RQ-PCR of less than 10% at 3 months of treatment predicts for achievement of complete cytogenetic remission and for overall survival and progression-free survival.47,48 The IRIS study was highly influential in shaping management of chronic myeloid leukaemia, with imatinib rapidly becoming the treatment of choice for newly diagnosed patients.6 However further research has shown that about 60% of patients remain on imatinib at 5 years. The main reasons for discontinuation are absence of efficacy (primary resistance), loss of previously obtained responses (acquired resistance), and/or intolerance to therapy. Several mechanisms of primary and acquired resistance, not necessarily mutually exclusive, have been identified including amplification of the BCR-ABL1 gene, overexpression of the multidrug resistant P-glycoprotein (MDR1) and low activity of the drug influx transporter, OCT1.49–52 However, the more frequent mechanism seems to be the development of point mutations in the Abl1 kinase domain, which results in decreased binding of TKI.53

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

5

Seminar

Kinase domain mutations were first described in 11 patients in advanced phase who relapsed on imatinib; six of whom had an identical cytosine to thymidine mutation at Abl1 nucleotide 944 resulting in a single aminoacid change at position 315, later designated T315I.53 So far more than 90 different nucleotide substitutions have been described, although 15 aminoacid substitutions account for more than 85% of the mutations observed in clinical practice.54 The functional relevance of these mutations is as yet unclear, in particular as to whether they contribute to disease progression (perhaps by conferring a growth advantage to affected cells) or are simply a surrogate marker of increased genomic instability associated with advanced disease. The mutations are not induced by TKI exposure but are selected through treatment to form an increasing proportion of the leukaemic cells, finally manifesting as drug resistance and being relatively easily detected by direct sequencing. Attempts to detect mutations at diagnosis are of little value in chronic phase, of similarly little value is routine screening for mutations in patients who are responding well to treatment (MR³, or complete cytogenetic remission). By contrast, mutation analysis is mandated in any patient with acquired resistance or who progresses to advanced phase disease, and can direct subsequent treatment. This topic has recently been extensively reviewed by a subgroup of the European Leadership Network expert consensus group.55

Second generation TKIs The identification of imatinib resistance led to a focused effort to develop additional TKIs with efficacy against kinase specific mutations. Dasatinib and nilotinib entered clinical trials within 12 months of each other and bosutinib some 2 years later. Dasatinib is an oral dual Src-Abl1 kinase inhibitor, given once daily. The phase 1 study of dasatinib 140 mg daily in 84 patients who did not respond to imatinib showed complete cytogenetic remission in 35% of patients in chronic phase and acceleration, and temporary haematological and cytogenetic responses in blast crisis. Responses were similar in patients with or without mutations, but were absent in those with the T315I mutation.56 A phase 2 study of 387 patients in chronic phase showed complete cytogenetic remission rates of 40% and 75% at 15 months in imatinib resistance and intolerance, respectively.57 Subsequently, a randomised phase 2 study of varying doses and dose schedules of dasatinib showed equivalent efficacy, but less toxicity with a dose of 100 mg once daily—now the recommended dose.58 A 5-year update confirmed that complete cytogenetic remission and MR³ once obtained, seem durable.59 Overall survival of imatinib-resistant and intolerant individuals were 78% and 82%, respectively, but it is worth noting that only 30–35% of patients remained on dasatinib at 5 years, and that most patients 6

requiring second line therapy will require a further change of therapy.60 Nilotinib, also an orally active aminopyrimidine, was developed from imatinib, by crystallographic analysis of compounds binding to imatinib resistant Bcr-Abl1 mutants. Nilotinib is taken twice daily with food restrictions because bioavailability increases markedly with concomitant high fat intake. Results from the phase 1 study in imatinib resistance were similar to those of dasatinib in that 35% of patients in chronic phase achieved cytogenetic responses.61 The phase 2 study of 321 patients in chronic phase with imatinib resistance, imatinib intolerance, or both, also replicated the dasatinib results with a complete cytogenetic remission rate of 45%, a 4 year overall survival of 78%, and a 4-year progression-free survival of 57%. As seen with dasatinib, only 31% of patients remained on nilotinib.62 Bosutinib is also an oral dual Src-Abl1 kinase inhibitor, given once daily. The phase 1/2 study in patients who had failed two or three previous TKIs resulted in complete cytogenetic remission in 24% of patients, 2 year estimated progression-free survival of 73%, and overall survial of 83%. At a median follow-up of 28 months, 29% of patients remained on bosutinib.63 Bosutinib was subsequently tested in 286 patients with imatinib resistance or intolerance, with 47% achieving complete cytogenetic remission. At 3 years, about 40% of patients remained on bosutinib and overall survival at 2 years was 88% in the imatinib resistant population and 98% in the imatinib intolerant population.64 For patients failing imatinib, all three second generation TKIs are useful, with perhaps as many as 40% of patients achieving durable complete cytogenetic remission. Several groups have tried to identify factors that might predict response. Milojkovic and colleagues65 showed that low Sokal score at diagnosis, previous cytogenetic responses to imatinib, and absence of cytopenias on imatinib to be influential. Jabbour and colleagues66 identified greater than 65% Ph-negativity within 12 months, baseline haemaglobin less than 120 g/L, baseline basophils less than 4%, and absence of mutations with low sensitivity to nilotinib at baseline as factors associated with improved progression-free survival in patients treated with nilotinib after imatinib resistance or intolerance. The realisation that the best outcomes on imatinib are strongly associated with rapid falls in tumour load, as measured by RQ-PCR levels at 3 months,48,49 prompted similar analyses for second generation TKI in second line.67,68 In all cases a similar pattern emerged and the most powerful predictor of complete cytogenetic remission is an RQPCR level less than 10% after 3 months of therapy. This finding has clinical use because it allows patients not responding to TKIs to be offered allogeneic stem cell transplantation early rather than risking disease progression with prolonged therapy and multiple changes of TKIs.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

Seminar

Choice of second generation TKIs for second line therapy All three drugs seem equally efficacious in the second line setting and only two criteria help to guide choice. First, a small number of kinase domain mutations are sensitive to one or other of the second generation TKIs. These mutations emerged in the phase 2 studies in imatinib failure, either through absence of efficacy in patients with certain pre-existing mutations or by identification of new mutations at the time of resistance to second generation TKI.69,70 For instance, patients with the imatinib-resistant F317L/V/I/C and G252H mutations are relatively insensitive to dasatinib and those with imatinib-resistant T253H, E255K/V, and F317L/V/I/C mutations are poorly sensitive to nilotinib. The V299L mutation, sensitive to nilotinib, was identified in patients resistant to, or relapsing on, dasatinib. The second criterion is the toxicity profile of each of the second generation TKI. Pre-existing comorbidities are clearly important in the selection of second and subsequent line drugs, but as always these decisions must be reached after balancing the risk of drug sideeffects against disease progression.

Third generation TKIs Ponatinib is described as third generation because it is the only family member with activity against T315I. The phase 1 study showed impressive activity in a group of heavily pretreated patients with 63% achieving complete cytogenetic remission.71 The phase 2 study enrolled patients in all stages of disease and subdivided these according to the presence or absence of the T315I mutation. Although most patients had received two or more previous TKIs, the results were encouraging. Within chronic phase, 46% achieved complete cytogenetic remission and greater response rates were seen in younger patients who had received less previous TKIs and with a shorter time from diagnosis to receiving ponatinib.72 Clinical efficacy against T315I was confirmed. A phase 3 randomised study of ponatinib and imatinib in newly diagnosed patients began in 2013, but was closed a few months later because maturing data from the phase 2 study suggested an increased incidence of arterial thrombotic events in patients given ponatinib.72 For this reason further development of ponatinib as front-line treatment for chronic phase disease is now on-hold pending further information about toxicity.

Management of newly diagnosed patients The choice of drug for newly diagnosed patients is one of the major dilemmas in chronic myeloid leukaemia, because imatinib, dasatinib, and nilotinib are all licensed for this indication. The outcome for patients treated with imatinib are well established through regular updates from the IRIS study73 together with the use of imatinib 400 mg daily as the standard arm of clinical trials investigating increased imatinib doses,74,75 combinations of imatinib with interferon or cytarabine,76,77 or second

generation TKIs78–81 (appendix). About 70–80% of patients will achieve durable complete cytogenetic remission. However, long-term follow-up within IRIS reported imatinib discontinuation in 37% of patients at 5 years and 45% of patients at 8 years.43 Some patients discontinued because of commercial availability, but others because of primary or acquired resistance and adverse events. Chronic low-grade debilitating side-effects82 lead to imatinib discontinuation because second generation TKIs can offer equivalent efficacy with reduced toxicity. All three second generation TKIs have completed phase 3 randomised studies against imatinib. Their major benefit compared with imatinib is the speed of achievement of deep responses—ie, MR³, MR⁴, and MR⁴·⁵—probably in a higher proportion of patients. In the DASISION study,79 at 24 months, complete cytogenetic remission rate was 86%, MR³ rate was 64%, and MR⁴·⁵ rate was 17% for dasatinib, and 82%, 46%, and 8% for imatinib. Rates of progression to advanced phase were 2·2% on dasatinib and 5% on imatinib (p=non significant).83 At 3 years, the MR⁴ and MR⁴·⁵ rates were 35% and 22% for dasatinib and 22% and 12 % for imatinib (p<0·01). Rates of progression to advanced phase at 3 years were 3% on dasatinib and 5% on imatinib.84 These results were confirmed in a north American study of identical design.85 Similar outcomes were obtained with nilotinib in the ENESTnd86 study in which nilotinib 300 mg twice daily or 400 mg twice daily were compared with imatinib. The 300 mg twice daily dose had similar efficacy but reduced toxic effects compared with 400 mg twice daily. At 2 years, complete cytogenetic remission rates were 87% for nilotinib 300 mg twice daily and 77% for imatinib.87 At 3 years, the MR⁴ and MR⁴·⁵ rates were 73% and 32% for nilotinib and 53% and 15% for imatinib. Rates of progression to advanced phase at 3 years were 0·7% on nilotinib 300 mg twice daily and 4·2% on imatinib.79 In the BELA study,81 patients were randomly assigned to bosutinib 500 mg once daily or imatinib 400 mg once daily. Complete cytogenetic remission rates at 12 months were similar, at 70% for bosutinib and 68% for imatinib, but MR³ rates were improved at 41% for bosutinib compared with 27% for imatinib. The discontinuation rates for all study drugs were similar at about 30% at 2 years, showing not only a slightly increased incidence of side-effects with second generation TKIs but perhaps an unwillingness of patients and physicians to tolerate adverse events when alternative drugs are readily available. However, imatinib remains the most popular first line therapy, predominantly because of efficacy in the majority, but also because after more than 14 years experience, severe or late unexpected toxic effects have not occurred. By contrast, nilotinib and ponatinib are associated with an increased risk of vascular obstruction,88,89 and dasatinib might induce, albeit infrequently, pulmonary hypertension.90 Until these risks have been substantiated and quantified, restricting the

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

See Online for appendix

7

Seminar

use of second generation TKIs for patients who are not responding optimally to imatinib or with high risk prognostic scores at diagnosis seems reasonable. A further contributing factor is cost; generic imatinib should be widely available within 2–3 years and this together with awareness that patients not responding to imatinib can be recognised by RQ-PCR assays within 3–6 months of treatment, suggest first-line imatinib as the most cost-effective strategy.

Identification and management of non-responding patients In the recommendations of 20066 and 2009,42 the European Leukaemia Net consensus group categorised responses according to the achievement or not of haematological, cytogenetic, and molecular responses at certain times after the start of treatment and created four groups comprising optimal, suboptimal, warning, and failing.6 The objective was to identify patients in whom the initial treatment should be continued (optimal), those who should be changed to an alternative therapy (failing), and those whose response was less than ideal (suboptimal and warning) but for whom there was no evidence that a change of therapy would alter outcome. In 2006, the only readily available TKI was imatinib and the only useful alternative therapy was allogeneic stem cell transplantation, so the European Leukaemia Net were anxious not to recommend a treatment carrying a substantial risk of mortality and morbidity if it were unnecessary. By 2009, the second generation TKIs were known to be effective and were readily available for patients failing imatinib and were incorporated into the guidelines.42 Because Panel 3: Changes in the European Leukaemia Net consensus group recommendations 201391 compared with the 200942 version • Imatinib, dasatinib, and nilotinib are all recommended for first line use • The definition of response requires the use of cytogenetic and molecular monitoring • The concept of so-called suboptimal responses has been deleted • Optimum responses are defined as molecular: BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0·1% from 12 months onward, and cytogenetic: >65% Ph negativity (PCyR) at 3 months and CCyR from 6 months • Failure is defined as molecular: BCR-ABL1 transcript levels >10% at 6 months and >1% from 12 months onward, and cytogenetic: no CyR (Ph+ >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months • Between optimal and failure there is a category defined as “warning” suggesting that frequent and vigilant monitoring is required PCyR=partial cytogenetic response. CCyR=complete cytogenetic remission.

8

second generation TKIs are now licensed for frontline use and because of the finding that patients less likely to respond well can be identified 3 months from start of therapy, the recommendations were recently updated.91 Panel 3 shows the major changes in the recently updated guidelines. The European Leukaemia Net consensus group have not recommended a change of therapy for patients with RQ-PCR greater than 10% at 3 months, despite strong evidence47,48 that this predicts for poor responses. The group argued that as yet, there is no evidence that a change of therapy at this point will change outcome. Additionally, the difference in overall survival of patients with BCR-ABL1 transcript levels less than 10% or greater than 10% at 3 months is only about 10%, suggesting that some patients might be changed unnecessarily at a very early timepoint to drugs that in the long term might prove to be more toxic than imatinib.

Managing side-effects All TKIs have a similar spectrum of toxic effects (table 4), but with some clear distinctions, which have been attributed to the varying levels of inhibition of the so-called off-target kinases (appendix). When imatinib was the only drug available, many side-effects were managed by temporary dose cessation, dose reduction, and supportive care. Cytopenias can be supported with erythropoietin and granulocyte-colony stimulating factor and platelet transfusions. Severe rashes and liver toxicity sometimes resolve with a short course of corticosteroids. Nowadays, the occurrence of grade 3/4 side-effects usually prompts a change to an alternative TKI, and most patients find at least one of the drugs to be free of severe side-effects. More problematic are the chronic grade 2 adverse effects, often in the form of chronic fatigue, which negatively affect quality of life and can affect compliance;94 these might respond to a change of TKI. In the past 3 years, more serious side-effects with second generation and third generation TKIs have been reported.72,88,89,90 All have cardiac toxicity and care must be taken in patients with a history of heart disease with special reference to the concomitant use of drugs causing QT prolongation.82,95 Dasatinib and, to a lesser extent, bosutinib cause pleural effusions, which can be managed by dose reduction but can also require a change of drug.96,97 Dasatinib is associated with a low incidence of pulmonary hypertension, which is not always reversible on drug withdrawal.90 An increased incidence of cardiovascular and cerebrovascular and peripheral arterial occlusive disease have been reported with both nilotinib and ponatinib, although many affected patients had predisposing risk factors.89,89 Diabetic control often improves on imatinib and dasatinib, but worsens on nilotinib.82,98 Other serious side-effects include hepatitis and pancreatitis, showing that close follow-up and investigation of new symptoms is necessary throughout life.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

Seminar

Imatinib

Dasatinib

Nilotinib

Bosutinib

Ponatinib

All grades

Grade 3/4

All grades

Grade 3/4

All grades

Grade 3/4

All grades

Grade 3/4

All grades

Grade 3/4

Fatigue

++++

+

+++

+

++++

-

NR

NR

++++

++

Rash

++++

++

+++

+

++++

-

++++

++

++++

++

Headache

+++

-

++++

-

++++

-

++++

++

++++

++

Myalgia and arthralgia

+++++

-

++++

-

NR

NR

++

-

++++

++

Bone pain

+++

++

NR

NR

NR

NR

++

-

NR

NR

Diarrhoea

++++

++

++++

+

+++

+

+++++

++++

NR

NR

Nausea

++++

-

++++

-

+++

+

++++

++

++++

+

Vomiting

+++

-

+++

-

++

-

++++

++

NR

NR

Abdominal pain

++

-

NR

NR

NR

NR

++++

++

++++

+++

Pancreatitis

+

+

NR

NR

++

++

NR

NR

+++

+++

Bleeding events (GI, CNS)

+

+

++

++

++

+

NR

NR

NR

NR

Oedema

++++

++

++++

++

+++

-

+++

++

NR

NR

Pleural effusion

++

+

++++

++

++

+

NR

NR

NR

NR

PAH

NR

NR

+

+

NR

NR

NR

NR

NR

NR

QT prolongation

+

NK

++

NK

++

NK

NR

NR

NR

NR

Hypertension

NR

NR

NR

NR

NR

NR

NR

NR

+++

++

PAOD

-

-

NR

NR

++

++

NR

NR

++++

++++

Elevated lipase

++++

+++

NG

-

++++

+++

++++

+++

++++

++++

Elevated ALT

++++

++

NG

+

+++++

+++

+++++

++++

++++

++

Low phosphate

+++++

++++

NG

+++

++++

+++

++++

++

NR

NR

Raised glucose

-

-

-

-

++++

+++

-

-

NR

NR

Anaemia

+++++

+++

+++++

++++

++++

++

+++++

+++

+++

+++

Neutropenia

+++++

++++

+++++

++++

++++

+++

++++

++++

++++

++++

Thrombocytopenia

+++++

++++

+++++

++++

++++

+++

++++++

++++

++++

++++

Abn platelet function

+++++

NK

+++++

NK

-

-

++++

NK

NR

NR

LGL expansion

NR

NR

++++

NK

NR

NR

NR

NR

NR

NR

Data derived from studies of first line use with the exception of ponatinib (so far used only as second or subsequent line) and rare events such as PAH, PAOD, and abnormal platelet function.72,78,79,82,83,86,92,93 +=<1% of patients. ++=1–5%. +++=5–10%. ++++=10–50%. +++++=50–100% =specifically reported as absent. NR=not reported. GI=gastrointestinal. PAH=pulmonary arterial hypertension. NK=effect of side-effect not known. PAOD=peripheral arterial occlusive disease. NG=data not given. ALT=alanine transaminase. Abn=abnormal. LGL=large granular lymphocytes.

Table 4: Most frequently reported side-effects of tyrosine-kinase inhibitors

Stopping treatment When TKIs became available, all believed that they would be administered for life. In 2010, Mahon and colleagues99 reported a trial of stopping therapy in 100 patients who had satisfied very stringent criteria of having had molecularly undetectable disease for at least 2 years. About 40% of the patients stopped have not had molecular recurrence to date. Most recurrences occurred within 6 months, and all patients regained excellent responses on restarting therapy. These observations have recently been confirmed in a smaller study.100 Because most patients who discontinue therapy have at least molecular recurrence, despite having deep and durable responses at the time of stopping, monitoring of such patients by frequent RQ-PCR is important. Ideally, all therapy discontinuation should continue to take place within clinical trials until the long-term outcome is better delineated. The ability to stop lifelong treatment in a proportion of patients is welcome information, however few patients have so far achieved molecularly undetectable

disease and are eligible for discontinuation.101 A 2013 publication suggests that up to a third of patients who receive imatinib from diagnosis achieve durably undetectable disease at 8 years.102 A more encouraging result has recently been reported from the German CML IV study group, which compared imatinib 400 mg once daily with imatinib 800 mg once daily or imatinib in combination with cytarabone or interferon α. The cumulative incidence of MR⁴·⁵ across all arms of the study was 70% at 9 years.103 Notably, molecularly undetectable disease is not necessarily indicative of complete absence of leukaemia, it simply means that the level of residual disease is below the limits of detection of the RQ-PCR assay. More sophisticated testing with patient-specific DNA-based PCR suggests that residual disease can be present, but is seemingly controlled by other mechanisms, presumably immunological.104,105 However, awareness that patients can regain excellent responses has been helpful for female patients wishing to become pregnant. The use of imatinib at the time of

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

9

Seminar

conception is associated with an increased incidence of congenital abnormalities,106 but now patients with deep molecular responses can be somewhat reassured that temporary cessation of treatment to have children should not jeopardise their long-term health. Because second generation TKIs used first line induce deep molecular responses more rapidly than imatinib, there is speculation that this will increase the numbers of patients able to stop therapy but this remains to be proven.

Advanced phase disease Responses to all TKIs in advanced phase are predictably less impressive than in chronic phase. 31% of patients in acceleration phase treated with nilotinib attained complete haematological response and complete cytogenetic remission in 20%, with 83% of those achieving complete cytogenetic remission sustaining this at 12 months. The estimated overall survival at 24 months was 67%.107 At 14 months on dasatinib, the equivalent response of complete haematological response was 45% and the complete cytogenetic remission was 32%, and the estimated overall survival at 12 months was 82%.108 Acceleration is highly heterogeneous and this probably explains why some patients achieve durable and deep responses. Other patients will benefit from early allogeneic stem cell transplantation where long-term survival of 25–40% have been reported.7,23 Unfortunately, factors predicting good responses to TKI in accelerated phase have not yet been identified, and a reasonable compromise would be a 3 month trial of a TKI at which time the absence of a substantial reduction in tumour load would indicate allogeneic stem cell transplantation. Results in blast crisis are less encouraging: roughly 30% of patients achieved complete cytogenetic remission on nilotinib or dasatinib but responses were short lived with median progression-free survival for myeloid blast crisis at 8 months and overall survival 12 months and for lymphoid blast crisis at 3 months for progession-free survival and 6 months for overall survival.109,110 Bosutinib and dasatinib are licensed for acceleration and blast crisis phases, but nilotinib only for accelerated phase. In a phase 2 study of ponatinib, complete cytogenetic remission was observed in 24% in accelerated phase and in 18% in blast crisis. Again, little evidence was observed for an improvement in outcome of blast crisis with median progression-free survival of 4 months and median overall survival of 7 months.72 TKIs are now used in combination with acute leukaemia-like combination chemotherapy to restore a second chronic phase and offer a window of opportunity for allogeneic stem cell transplantation,111 as in general, chronic myeloid leukaemia blast crisis remains a fatal disease.

Conclusions and future directions In less than 10 years, chronic myeloid leukaemia has changed from a largely incurable disorder to a disease compatible with a normal lifespan. Characterised by a 10

single molecular event, chronic myeloid leukaemia shows the importance of understanding the molecular pathogenesis and the potential of targeted therapies. The goal of treatment has shifted from prolonging survival to maintaining quality of life, which will increasingly be dependent on appropriate selection of TKI to minimise toxic effects and careful management of comorbidities. For many patients the future might involve domiciliary RQ-PCR monitoring, drug delivery with infrequent hospital or telemedicine visits. Despite these remarkable achievements, three contrasting problems remain. First, at present, minimum residual disease is detectable in most responders, suggesting the presence of a quiescent leukaemic stem cell. Eradication of residual stem cells will affect the second question, how can we increase the proportion able to discontinue treatment long term? Finally, and sadly, 10–15% of patients remain resistant to TKIs and at risk of disease progression. Understanding the mechanisms of blast crisis will be the challenge of the next decade. Contributors JFA did the literature search, interpreted the data, provided personal recommendations, and wrote the manuscript. Declaration of interests JFA received research funding from Novartis, honoraria for advisory board, and lecture fees from Novartis, Bristol-Myers Squibb, Ariad, Pfizer, and Teva. Acknowledgments JFA acknowledges support from the NIHR Biomedical Research Centre funding scheme. References 1 Huang XL, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer 2012; 118: 3123–27. 2 Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290–93. 3 Goldman JM, Melo JV. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1084–86. 4 Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 2012; 87: 1037–45. 5 Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. In: WHO Classification of Tumours, vol 2. Geneva: World Health Organization, 2008. 6 Baccarani M, Saglio G, Goldman J, et al, and the European Leukemia Net. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood 2006; 108: 1809–20. 7 Khoury HJ, Kukreja M, Goldman JM, et al. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib era: a CIBMTR analysis. Bone Marrow Transplant 2012; 47: 810–16. 8 Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984; 63: 789–99. 9 Hasford J, Pfirrmann M, Hehlmann R, et al, and the Writing Committee for the Collaborative CML Prognostic Factors Project Group. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998; 90: 850–58. 10 Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011; 118: 686–92.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

Seminar

11

12 13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

Hoffmann VS, Baccarani M, Lindoerfer D, et al. The EUTOS prognostic score: review and validation in 1288 patients with CML treated frontline with imatinib. Leukemia 2013; 27: 2016–22. Conan-Doyle A. Notes on a case of leucocythaemia. Lancet 1882; 1882: 490. Chronic granulocytic leukaemia: comparison of radiotherapy and busulphan therapy. Report of the Medical Research Council’s working party for therapeutic trials in leukaemia. BMJ 1968; 1: 201–08. Bonifazi F, de Vivo A, Rosti G, et al, and the Europena Study Group on Interferon in Chronic Myeloid Leukemia, and the Italian Cooperative Study Group on CML, and the France Intergroup of CML, and the German CML Study Group, and the UK Medical Research Council Working Party on CML, and the Spanish CML Study Group, and the Australian CML Study Group, and the Swedish CML Study Group. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 2001; 98: 3074–81. Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating MJ, Gutterman JU. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med 1986; 314: 1065–69. Hehlmann R, Heimpel H, Hasford J, et al, and the The German CML Study Group. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 1994; 84: 4064–77. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330: 820–25. Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council’s Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet 1995; 345: 1392–97. Guilhot F, Chastang C, Michallet M, et al, and the French Chronic Myeloid Leukemia Study Group. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 1997; 337: 223–29. Fefer A, Cheever MA, Thomas ED, et al. Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. N Engl J Med 1979; 300: 333–37. Goldman JM, Baughan AS, McCarthy DM, et al. Marrow transplantation for patients in the chronic phase of chronic granulocytic leukaemia. Lancet 1982; 2: 623–25. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 1998; 338: 962–68. Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011; 117: 755–63. Apperley JF, Jones L, Hale G, et al. Bone marrow transplantation for patients with chronic myeloid leukaemia: T-cell depletion with Campath-1 reduces the incidence of graft-versus-host disease but may increase the risk of leukaemic relapse. Bone Marrow Transplant 1986; 1: 53–66. Kolb HJ, Mittermüller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–65. Mackinnon S, Papadopoulos EB, Carabasi MH, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 1995; 86: 1261–68. Dazzi F, Szydlo RM, Craddock C, et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 2000; 95: 67–71. Khouri IF, Keating M, Körbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–24. Crawley C, Szydlo R, Lalancette M, et al, and the Chronic Leukemia Working Party of the EBMT. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 2005; 106: 2969–76.

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

Gratwohl A, Hermans J, Goldman JM, et al, and the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet 1998; 352: 1087–92. Saussele S, Lauseker M, Gratwohl A, et al, and the German CML Study Group. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 2010; 115: 1880–85. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–66. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–37. Kantarjian H, Sawyers C, Hochhaus A, et al, and the International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–52. O’Brien SG, Guilhot F, Larson RA, et al, and the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004. Cross NC, Feng L, Chase A, Bungey J, Hughes TP, Goldman JM. Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukemia patients after bone marrow transplantation. Blood 1993; 82: 1929–36. Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 2012; 26: 2172–75. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37. Hughes TP, Kaeda J, Branford S, et al, and the International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1423–32. Branford S, Fletcher L, Cross NCP, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008; 112: 3330–38. White HE, Matejtschuk P, Rigsby P, et al. Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. Blood 2010; 116: e111–17. Baccarani M, Cortes J, Pane F, et al, and the European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27: 6041–51. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon Vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood 2009; 114: 462. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26: 3358–63. Kantarjian HM, O’Brien S, Cortes J, et al. Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data. Cancer 2003; 98: 2636–42. Hughes TP, Hochhaus A, Branford S, et al, and the IRIS investigators. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010; 116: 3758–65. Hanfstein B, Müller MC, Hehlmann R, et al, and the SAKK, and the German CML Study Group. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012; 26: 2096–102.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

11

Seminar

48

49

50

51

52

53

54 55

56

57

58

59

60

61

62

63

64

65

66

12

Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 2012; 30: 232–38. le Coutre P, Tassi E, Varella-Garcia M, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000; 95: 1758–66. Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000; 95: 3498–505. Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1070–79. White DL, Radich J, Soverini S, et al. Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib. Haematologica 2012; 97: 907–14. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–80. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018–29. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from anexpert panel on behalf of European LeukemiaNet. Blood 2011; 118: 1208–15. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354: 2531–41. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008; 22: 1200–06. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26: 3204–12. Brummendorf TH, Shah NP, Cortes JE, et al. Long-term efficacy and safety of dasatinib 100 mg once-daily (QD) in patients with imatinib-resistant/intolerant chronic-phase chronic myeloid leukemia (CML-CP): 5-year follow-up from CA180-034. Onkologie 2011; 34: 263. Milojkovic D, Apperley JF, Gerrard G, et al. Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients. Blood 2012; 119: 1838–43. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542–51. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 2013; 27: 107–12. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012; 119: 3403–12. Gambacorti-Passerini C, Brümmendorf TH, Kim DW, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: minimum 24-month follow-up. Am J Hematol 2014; 89: 732–42. Milojkovic D, Nicholson E, Apperley JF, et al. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica 2010; 95: 224–31. Jabbour E, le Coutre PD, Cortes J, et al. Prediction of outcomes in patients with Ph+ chronic myeloid leukemia in chronic phase treated with nilotinib after imatinib resistance/intolerance. Leukemia 2013; 27: 907–13.

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

Branford S, Kim DW, Soverini S, et al. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol 2012; 30: 4323–29. Saglio G, Kantarjian HM, Shah N, et al. Early Response (Molecular and Cytogenetic) and Long-Term Outcomes in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Analysis of DASISION 3-Year Data. Blood 2012; 120. Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronicphase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009; 114: 4944–53. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009; 27: 4204–10. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367: 2075–88. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013; 369: 1783–96. Druker BJ, Guilhot F, O’Brien SG, et al, and the IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–17. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 2010; 28: 424–30. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 2010; 28: 424–30. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011; 29: 1634–42. Preudhomme C, Guilhot J, Nicolini FE, et al, and the SPIRIT Investigators, and the France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC). Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010; 363: 2511–21. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012; 26: 2197–203. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119: 1123–29. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 2012; 30: 3486–92. Steegmann JL, Cervantes F, le Coutre P, Porkka K, Saglio G. Off-target effects of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic myeloid leukemia. Leuk Lymphoma 2012; 53: 2351–61. Hochhaus A, Shah NP, Cortes JE, et al. Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up. J Clin Oncol 2012; 30: 232-38 Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362: 2260–70. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123: 494–500. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012; 120: 3898–905.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

Seminar

86

87

88

89

90

91

92

93

94

95

96

97

98

99

Saglio G, Kim DW, Issaragrisil S, et al, and the ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362: 2251–59. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12: 841–51. Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011; 86: 533–39. Kim TD1, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013; 27: 1316–21. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125: 2128–37. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–84. Quintás-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009; 114: 261–63. Neelakantan P, Marin D, Laffan M, Goldman J, Apperley J, Milojkovic D. Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy. Haematologica 2012; 97: 1444. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28: 2381–88. Fullmer A, Kantarjian H, Cortes J, Jabbour E. Dasatinib for the treatment of chronic myeloid leukemia. Expert Rev Hematol 2011; 4: 253–60. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol 2008; 141: 745–47. Quintas-Cardama A, Kantarjian HM, Munden R, et al. Pleural effusion in patients (pts) with chronic myelogenous leukemia (CML) treated with dasatinib after imatinib failure. J Clin Oncol 2007; 25: 3908–14. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract 2011; 17: 197–202. Mahon FX, Réa D, Guilhot J, et al, and the Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010; 11: 1029–35.

100 Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013; 122: 515–22. 101 Milojkovic D, Gerrard G, Paliompeis C, et al. The natural history of RTQ-PCR levels after the achievement of complete molecular remission (CMR): implications for “stopping” studies. Blood 2011; 118: 605 (abstr). 102 Branford S, Ross D, Prime J, et al. Early molecular response and female sex strongly predict achievement of stable undetectable BCR-ABL1, a criterion for imatinib discontinuation in patients with CML. Blood 2013; 121: 3818–24. 103 Hehlmann R, Müller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol 2014; 32: 415–23. 104 Ross DM, Branford S, Seymour JF, et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 2010; 24: 1719–24. 105 Sobrinho-Simões M, Wilczek V, Score J, Cross NCP, Apperley JF, Melo JV. In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib. Blood 2010; 116: 1329–35. 106 Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111: 5505–08. 107 le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 2012; 26: 1189–94. 108 Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 2009; 27: 3472–79. 109 Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 2012; 26: 959–62. 110 Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 2008; 22: 2176–83. 111 Milojkovic D, Ibrahim A, Reid A, Foroni L, Apperley J, Marin D. Efficacy of combining dasatinib and FLAG-IDA for patients with chronic myeloid leukemia in blastic transformation. Haematologica 2012; 97: 473–74.

www.thelancet.com Published online December 5, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62120-0

13