Chronic myeloid leukemia: a model for oncology
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- Hehlmann, R., Berger, U. & Hochhaus, A. Ann Hematol (2005) 84: 487. doi:10.1007/s00277-005-1039-z
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Leukemias have traditionally served as model systems for research on neoplasia because of the easy availability of cell material from blood and marrow for diagnosis, monitoring and studies on pathophysiology. Beyond these more technical aspects, chronic myeloid leukemia (CML) became the first neoplasia in which the elucidation of the genotype led to a rationally designed therapy of the phenotype. Targeting of the pathogenetically relevant BCR-ABL tyrosine kinase with the selective kinase inhibitor imatinib has induced remissions with almost complete disappearance of any signs and symptoms of CML. This therapeutic success has triggered an intensive search for target structures in other cancers and has led to the development of numerous inhibitors of potential targets, which are being studied in preclinical and clinical trials worldwide. This review deals with some of the recent developments that have evolved since our last review in this journal in 2000 (Hehlmann R, Hochhaus A, Berger U, Reiter A (2000) Current trends in the management of chronic myelogenous leukemia. Ann Hematol 79:345–354).
KeywordsChronic myeloid leukemia Model for oncology Targeted therapy Imatinib in combination Evolution to blast crisis
Model disease: chronic myeloid leukemia
Chronic myeloid leukemia (CML) has served as a model for other cancers due to its multistep evolution with several defined stages (chronic phase, acceleration, blast crisis), its regular association with a defined cytogenetic translocation t(9;22)(q34;q11), the elucidation of molecular pathogenesis and the successful development of a molecular targeted therapy. The term leukemia was first coined by Virchow in 1845 [87, 88] when he realized the neoplastic nature of purulent matter (“weißes Blut”) in patients with what later was designated CML. Its origin in the bone marrow was deduced a few years later by Neumann . The detection of the Philadelphia chromosome in 1960  provided a marker that almost unequivocally defined the disease. In 1973, it was recognized that the basis of the Philadelphia chromosome was a reciprocal translocation between the long arms of chromosomes 9 and 22 . The molecular structure of this translocation was clarified in the early 1980s [2, 37], and in 1990 it was demonstrated that BCR-ABL transformed cells in vitro and that BCR-ABL-transfected marrow cells induced leukemia in mice . This demonstration of pathogenetic relevance of the BCR-ABL fusion gene led to the search for inhibitors and to the introduction of the tyrosine kinase inhibitor imatinib into clinical investigation and application in 1998 [14, 15]. The introduction of a rationally designed pharmacotherapy directed against a pathogenetically relevant target marks the preliminary end point of 140 years of attempts to treat and cure CML.
Medical treatment of CML
The first drug that was reported active in CML was arsenic in 1865 . This German report was confirmed by American authors in 1878 . It is an irony of pharmacotherapeutic development that currently arsenic is reintroduced into CML management as second-line treatment in combination with imatinib .
Treatment was purely palliative during the first century of CML treatment, which included splenic irradiation, various cytostatic agents of which busulfan was standard for almost three decades, and intensive combination therapy. Treatment intention became curative with the introduction of stem cell transplantation in the 1970s .
Phase I, II and III studies with imatinib
Druker et al. 2001a 
CP, IFN failure
HR in 53 of 54, CR in 29 of 54
Druker et al. 2001b 
Response, 21 of 38
Kantarjian et al. 2002 
CP, IFN failure, n=532
HR 95%, CR 60%, CCR 91%
Talpaz et al. 2002 
HR 34%, CCR 17%
Sawyers et al. 2002 
HR 7%, CCR 7%
Ottmann et al. 2002 
Lymphoid BC, n=8
O’Brien et al. 2003 
Primary CP, n=1106
HR 95% vs 69%
Imatinib vs IFN+ara-C
CR 87% vs 22%
CCR 79% vs 14%
In a phase III trial on 1,106 non-pretreated patients in early-phase CML randomized between imatinib and IFN in combination with low-dose ara-C, the imatinib group achieved complete hematologic remissions in 98% (vs 69% in the IFN group), partial cytogenetic remissions in 91% (vs 22%) and complete cytogenetic remissions in 84% (vs 14%) of cases (42 months data) . There was a slight superiority of progression-free survival in imatinib patients (96.7% vs 91.5%). The time to hematologic remission was much shorter with imatinib (about 90% after 3 months) than with IFN. Also, cytogenetic remissions were reached much faster but, similar to the effect observed under IFN, first cytogenetic remissions were also observed after 30 months. Similar to the effects observed with IFN, the achievement of complete cytogenetic remissions is followed in most patients by a continuous decline of BCR-ABL transcript levels, which continues after 30 months. Tolerability of imatinib was excellent, only 1–2% experienced grade 3–4 toxicity in contrast to IFN-treated patients in which up to 24% experienced severe fatigue or depression.
On the basis of survival data of IFN-treated patients with CML who achieved complete cytogenetic remissions, a 10-year-survival rate of 51% was estimated for imatinib-treated patients . It can be concluded that imatinib is superior to IFN with regard to response rate, progression-free survival and adverse effects. No definite data exist yet as to long-term survival and late toxicity, although prolongation of survival by imatinib seems probable.
Minimal residual disease
Molecular monitoring of BCR-ABL transcript levels with quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) technology in patients who have achieved a complete cytogenetic remission has become an important asset of long-term CML management. Real-time quantitative RT-PCR using specific fluorescent hybridization probes and standard procedures with internal controls allow a rapid and accurate analysis [19, 64].
Early reduction of BCR-ABL transcript levels predicts cytogenetic response and favorable clinical course in imatinib-treated chronic-phase patients with CML [62, 64, 89]. Low levels of residual disease have been associated with continuous remission. The degree of molecular response correlates directly with progression-free survival [42, 64]. The persistence of BCR-ABL transcripts even after prolonged imatinib treatment in most patients argues against a prospect of cure by imatinib alone and for additional therapeutic measures. Similar observations have been made earlier after allografting. Transplanted patients with complete disappearance of BCR-ABL transcripts within 6–12 months have been found to have excellent prospects for a successful transplantation outcome and probably cure. Transplanted patients with persistence of BCR-ABL transcripts, or reappearance of transcripts after initial disappearance, have an increased risk of relapse .
Mutations of the ATP-binding site of the BCR-ABL tyrosine kinase domain
Clonal evolution with aberrant karyotypes ultimately leading to blast crisis
Detailed sequence analysis has been performed to elucidate which mutations are responsible for the development of imatinib resistance. More than 30 different mutations have been recognized, which are detailed elsewhere . The prognostically most serious mutations concern the so-called “P-loop” domain of the tyrosine kinase. P-loop mutations have been associated with an especially poor prognosis , but cessation of imatinib therapy and alternative therapy with other drugs seem to be able to improve prognosis .
To increase imatinib dosage to 600 or 800 mg
To combine imatinib with other drugs of known anti-CML activity
To use new, more efficient BCR-ABL inhibitors
The increase of imatinib dosage has been previously shown to improve response in patients with accelerated disease. Accelerated disease was found to have higher response rates with 600 mg imatinib than with 400 mg . Kantarjian et al.  reported in a historical comparison that higher cytogenetic remission rates can be achieved in shorter time intervals with an imatinib dosage of 800 mg daily as compared with 400 mg in chronic phase CML. The disadvantage of the higher imatinib dose is a higher rate of adverse effects, in particular myelosuppression and fluid retention. It is unknown whether the effect of high dose imatinib is sustained and provides a survival benefit.
Imatinib in combination
Combinations of imatinib with other drugs have been extensively analyzed in vitro and have shown that a number of drugs are synergistic with imatinib in vitro [46, 55, 86]. Of particular interest were the combinations of imatinib with IFN or low-dose ara-C. The feasibility of the combinations of imatinib with IFN (Pegasys, PEG-Intron) and low-dose ara-C has been shown in phase I and II studies [1, 24, 38, 68].
On the basis of these studies, randomized trials were designed by national study groups in Germany, France, Spain, USA and the UK to compare imatinib monotherapy at 400 mg with imatinib in various combinations (IFN, ara-C) and dosages (600 and 800 mg).
Indications for allografting in CML 2004 (as suggested by transplanters of the German CML Study Group)
High-risk patients (new score; Hasford et al. 1998 )
Low transplantation risk (Gratwohl score 0–1 )
Definition of imatinib failure
No hematologic response within 3 months
No sufficient cytogenetic response (no minor response, Ph+ ≥95%) within 6 months with concomitant cytopenias that exclude imatinib dose escalation of imatinib to 600 or 800 mg daily at the 2 and 6 months of imatinib therapy checkpoints
No major cytogenetic response within 12 months (Ph+ ≥35%)
Loss of complete hematologic or any previously attained cytogenetic response
Rise of BCR-ABL transcript levels by at least one log in previously complete cytogenetic responders
In September 2003, the French study was started, which compares imatinib monotherapy at 400 mg vs imatinib at 600 mg vs imatinib plus IFN (Pegasys) vs imatinib plus low-dose ara-C. By February 2005, recruitment of 267 patients was reported. After an observation period, it is planned to reduce the study to two arms.
Also in 2003, a Spanish (PETHEMA) study was started comparing imatinib at increasing doses vs imatinib at standard dose plus low-dose IFN. By April 2005 recruitment of 118 patients was reported.
In autumn 2004, a US study was started, which compares dosages of imatinib at 400 vs 800 mg. This study plans the evaluation of hematologic, cytogenetic and molecular response rates after 1 year as primary study endpoints.
A UK study that will compare imatinib monotherapy at 400 mg vs imatinib at 800 mg vs imatinib plus IFN (Pegasys) is to start in 2005. This study will compare the 5-year-survival times of the three treatment arms.
A third approach to overcome imatinib response is the development of new, more efficient BCR-ABL tyrosine kinase inhibitors. Several new compounds have been reported (AMN107 of Novartis, BMS 354825 of Bristol-Myers Squibb , PD166326 of Sloan-Kettering , AP23464 of Ariad Pharmaceuticals ), two of which have entered clinical trials (AMN107 and BMS354825). Target structures of AMN107 are BCR-ABL, c-KIT and PDGFR, of BMS354825 BCR-ABL, c-KIT, PDGFR and SRC. For ABL inhibition, AMN107 is more than one log and BMS354825 more than two logs more potent than imatinib. Clinical trials with AMN107 and BMS354825 include both CML and BCR-ABL-positive ALL. BMS 354825 has been shown to retain activity against 14 of 15 imatinib-resistant BCR-ABL mutants .
Stem cell transplantation
Although allografting is still considered to be the only potentially curative approach to CML, transplantation numbers have dropped significantly in the imatinib era due to transplantation-associated mortality and morbidity . Transplantation-associated mortality during the first year ranges around 25% in two multicenter studies of the German CML Study Group (CML Studies III and IIIA). A trend towards lower mortality rates after related donor transplantations has been noted, but overall mortality seems to stay unchanged due to the higher proportion of unrelated donor transplantations and an increased age of transplanted patients. Categorization of patients according to transplantation risks, therefore, becomes increasingly important.
The realization that donor lymphocytes constitute the most relevant factor in eliminating residual disease in CML [51, 52] has led to a reduction of intensity of conditioning regimens before allografting [27, 61, 80]. Low-intensity conditioning allows allografting also in older patients and in patients with other thus far disqualifying conditions. Currently, this new approach is studied for long-term efficacy and cost-effectiveness in many centers as described above for CML Study IV. The favored procedure, at present, is that described by Or’s group  because of its favorable outcome results and because it does not require irradiation, which is not available everywhere.
Origin of CML and evolution to blast crisis
Although the pathogenetic relevance of the BCR-ABL translocation has been confirmed by the treatment response to imatinib beyond doubt, it remains unclear whether the BCR-ABL translocation represents the first step in pathogenesis and how the translocation is triggered. One possible explanation may be that certain translocations, similar to mutations, are not infrequent events, which normally are down-regulated, e.g. by immunosurveillance. The frequent observation of BCR-ABL sequences at very low levels in normal adults increasing with age supports such a mechanism. The capability of immunosurveillance to control and suppress BCR-ABL-positive cells is impressively demonstrated by the success of CML treatment with healthy donor T cells [5, 7, 52].
Similarly unclear is the evolution leading to acceleration and blast crisis. Several mechanisms are being discussed:
The BCR-ABL translocation, in addition to its anti-apoptotic effect, causes genetic instability, which predisposes to an increased probability of secondary genetic changes that may be lethal, irrelevant or have a proliferative advantage. These secondary chromosomal and/or molecular changes would increase genetic instability and predispose to more secondary changes. Such mechanisms are supported by cytogenetic and molecular findings observed in blast crisis. The chromosomal changes include a second Ph chromosome, trisomy 8, isochromosome 17q, trisomy 19, or complex aberrations as observed in 60–80% of blast crises. Of the mutational events, p53 mutations are of special interest, since they are observed in up to 30% of myeloid blast crises, and also p16/ARF and rb mutations, since they are observed in up to 50% of cases with lymphatic blast crises.
From these observations, Gilliland and Tallman  developed their mutation proliferation model of blast crisis, which postulates a differentiation stop, e.g. by C/EBPα inhibition and an activation of proliferation, e.g. by p16/ARF deletion with inhibition of p53 and rb. Activation of β-catenin in CML granulocyte–macrophage progenitors may enhance leukemic potential and proliferation .The stop of differentiation associated with an activation of proliferation would explain the clinical and morphological picture of blast crisis, but not, however, the rapidly progressive treatment resistance.
This could be explained by the aneuploidy model, which postulates that genetic instability induces chromosomal aberrations (aneuploidy) that conversely generate genetic instability [56, 74]. Genetic instability has been observed to be proportional to the degree of aneuploidy [17, 20, 90]. The aneuploidy model initially would not require mutational events. Abnormal growth behavior would be due to abnormal doses of normal genes. Observed mutations would be consequences of the abnormal proliferation behavior of cells due to aneuploidy. Multidrug resistance has been shown to segregate with karyotypic aberrations [17, 18], which would be compatible with what we observe in blast crisis. No drug resistance has been confirmed in normal diploid cells up to now.
Both models still await experimental confirmation. The high frequency of complex karyotypic aberrations in blast crisis, however, requires close scrutiny and systematic evaluation.
Targeted therapy in clinical oncology
The success of targeted therapy in CML has stimulated the search for similar targets and inhibitors in other cancers. The situation in CML is special because the target is of known pathogenetic relevance. No structure of proven pathogenetic relevance has been identified in any other cancer. Therefore, surrogate features are used that might serve as relevant targets such as a role in signal transduction, expression activity or defining surface antigenicity. Molecular targets meeting these criteria are mostly oncogene kinases, growth factor kinases or growth factor receptor kinases, surface antigens and other structures playing a role in signaling, such as the proteasome or the mTOR kinase.
Examples of targeted therapies in clinical oncology
Imatinib (Glivec), AMN107, BMS354825, AAP23464
Metastic breast cancer
Locally advanced head and neck cancer
Renal cell cancer
CML, GIST, breast–lung cancer (in combination)
Rapamycin, CCI-779 Everolimus (RAD001, Certican)
Farnesyl transferase/ras pathway
CML, lung cancer, breast cancer
Head and neck cancer
Examples of small molecule inhibitors (beyond BCR-ABL inhibitors) are the epidermal growth factor receptor (EGFR) inhibitors gefitinib (Iressa) and erlotinib (Tarceva), the inhibitor of vascular endothelial growth factor receptor (VEGFR) vatalanib, the proteasome inhibitor bortezomib (Velcade), the mTOR kinase inhibitors everolimus (RAD001, Certican) and CCI-779, and the farnesyl transferase inhibitors tipifarnib (Zarnestra) and lonafarnib (Sarasar).
Monoclonal antibodies have been successfully used in the past: trastuzumab (Herceptin) against HER2/neu, alemtuzumab (campath-1H, Mab-Campath) against CD52 and rituximab (Mabthera) against CD20, but more recently, monoclonals have been generated also against EGFR (Cetuximab, Erbitux) and VEGF (Bevacizumab, Avastin). Cetuximab has efficacy in metastatic colorectal carcinoma in combination with irinotecan (major response rate, 22.5% ). Bevacizumab in combination with chemotherapy has activity against metastatic colorectal, renal and non-small cell lung cancers [25, 43, 45].
The limitations of targeted therapy in solid cancers are due to the fact that the relevance of target structures for the respective cancers is uncertain. Therefore, it is not surprising that response rates and duration of response are limited. Gefitinib, for instance, shows responses in only 10–19% of patients with chemotherapy-refractory advanced non-small cell lung cancer [11, 22, 53]. The great advantage of this new treatment approach, however, is its low level of adverse reactions, which makes it a real progress as compared with conventional chemotherapy with cytostatics that in most cases is associated with severe toxicity.
The efficacy pattern of imatinib in gastrointestinal stromal tumors (GIST) has demonstrated that responsiveness correlates with the mutation pattern of the c-kit tyrosine kinase. Imatinib is best acting in patients with activating c-kit mutations but less efficient in patients with wild type c-kit and inefficient in case of mutations creating primary resistance by inhibiting imatinib binding . Activating mutations have also been described in the EGFR gene [60, 72], which are associated with response to gefinitib therapy. Such mutations leading to constitutive activation of c-kit or EGFR are equivalent to the activation of ABL by juxtaposition to BCR in CML.
The example of imatinib-resistant CML with the expansion of clones harboring BCR-ABL mutations associated with imatinib resistance has been confirmed in relapsing GIST patients with metastases, which are characterized by the appearance of additional c-kit mutations associated with imatinib resistance . Such mutations have not been described in the EGFR gene as yet. However, experience with imatinib resistance in CML has paved the way for applications to solid cancers.