Annals of Hematology

, Volume 84, Issue 8, pp 487–497

Chronic myeloid leukemia: a model for oncology

Review Article

DOI: 10.1007/s00277-005-1039-z

Cite this article as:
Hehlmann, R., Berger, U. & Hochhaus, A. Ann Hematol (2005) 84: 487. doi:10.1007/s00277-005-1039-z


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).


Chronic 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 [65]. The detection of the Philadelphia chromosome in 1960 [66] 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 [75]. 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 [13]. 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 [21]. This German report was confirmed by American authors in 1878 [59]. It is an irony of pharmacotherapeutic development that currently arsenic is reintroduced into CML management as second-line treatment in combination with imatinib [54].

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 [81].

A prolongation of survival can be offered by interferon α in combination with hydroxyurea or low-dose ara-C, particularly in low-risk patients and in patients who achieve a cytogenetic remission (see below). Women may have a survival advantage over men [4]. Observation time on imatinib is still too short to allow any definite conclusion on prolongation of survival although the high, complete cytogenetic remission rates associated with major molecular responses in many patients make a life-prolonging effect by imatinib probable. Meanwhile, the second generation of much more potent BCR-ABL tyrosine kinase inhibitors awaits clinical evaluation. The development of CML therapy is depicted in Fig. 1. A similar situation regarding targeted therapy now exists for multiple cancers, which makes oncology the medical subspecialty with the highest number of new drugs awaiting clinical evaluation and registration worldwide (395 drugs in clinical trials for cancer vs 122 for heart diseases and stroke and 176 for neurological disorders, Lee Hartwell, Plenary Science of Oncology Lecture, ASCO, June 2004).
Fig. 1

Historical development of CML therapy. Bold framing indicates actual therapy options

Interferon α

Interferon α (IFN) in combination with hydroxyurea or low-dose ara-C has been shown to prolong survival in CML. The randomized comparison with busulfan and hydroxyurea by the German CML Study Group is shown in Fig. 2. Prolongation of survival is most pronounced in low-risk patients and in patients who achieve a complete cytogenetic remission. In a meta-analysis of 1,400 patients with CML treated with IFN in early chronic phase, low-risk patients, according to the new CML score, had a 10-year survival of 40% (for score see legend to Fig. 3) [31]. Two meta-analyses on 500 patients with complete IFN-induced cytogenetic remissions showed a 10-year survival of 65–80% depending on the risk profile [6, 49, 84]. IFN is life prolonging also in the elderly at lower dosage [3]. The dosage of IFN probably is not critical since dosage requirement declines over time [34] and since a daily dose of 2 million units (MU) gives similar results as 4–5 million units (MU) as shown in a randomized comparison [50]. The prolongation of survival by IFN seems to be mediated by a protracted immunological effect, as demonstrated by the appearance of first cytogenetic remissions as late as 7 or more years after start of IFN treatment [33, 84] and by a continuous decline of BCR-ABL transcript levels under IFN therapy after a complete cytogenetic remission has been achieved [41, 64]. Marrow fibrosis may serve as an indicator of therapy failure [10]. A drawback of IFN therapy is the adverse effects in many patients, which, although never life threatening, may be cumbersome and compromise quality of life. Pegylated IFN preparations (Pegasys, PEG-Intron) with injections once weekly appear to be better tolerable and even more effective than conventional IFN, but randomized studies to prove this point were terminated too early to be conclusive [58, 63]. Due to its proven life-prolonging effect, however, IFN in combination with hydroxyurea (or low-dose ara-C) still has to be considered first-line treatment.
Fig. 2

IFN vs busulfan vs hydroxyurea, 10 year outcome, German CML Study II [33]

Fig. 3

Meta-analysis of 1400 patients with CML treated with IFN in early chronic phase [31]. New score=[0.6666×age (0 when age <50; 1 otherwise)+0.042×spleen size (cm below costal margin)+0.0584×blasts (%)+0.0413×eosinophils (%)+0.2039×basophils (0 when basophils <3%; 1 otherwise)+1.0956 × platelet count (0 when platelets <1,500×109/l; 1 otherwise)]×1,000


The introduction of imatinib into CML therapy marks a major advance in CML treatment with regard to efficacy and lack of adverse reactions. Its mechanism of action is blocking the ATP-binding site of the BCR-ABL tyrosine kinase [78] with high affinity and high specificity. After imatinib had been shown to inhibit BCR-ABL-positive cell lines in vitro [16], phase I trials started in 1998 and phase II trials in 1999. Imatinib showed good efficacy and tolerability in patients who had failed IFN treatment [15, 47]. The beneficial effect of imatinib was demonstrated in the chronic phase [47], advanced phase [14, 82] and in blast crisis [77] as well as in Philadelphia positive acute lymphatic leukemia (ALL) [71, 77]. A summary of these studies is provided in Table 1.
Table 1

Phase I, II and III studies with imatinib


Disease stage


Phase I

 Druker et al. 2001a [15]

CP, IFN failure

HR in 53 of 54, CR in 29 of 54

 Druker et al. 2001b [14]


Response, 21 of 38

Phase II

 Kantarjian et al. 2002 [47]

CP, IFN failure, n=532

HR 95%, CR 60%, CCR 91%

 Talpaz et al. 2002 [82]

AP, n=235

HR 34%, CCR 17%

 Sawyers et al. 2002 [77]

BC, n=260

HR 7%, CCR 7%

 Ottmann et al. 2002 [71]

ALL, n=48

HR 29%

Lymphoid BC, n=8

HR 38%

Phase III

 O’Brien et al. 2003 [67]

Primary CP, n=1106

HR 95% vs 69%

Imatinib vs IFN+ara-C

CR 87% vs 22%


CCR 79% vs 14%

CP chronic phase, BC blast crisis, AP accelerated phase, HR complete hematologic remission, CR cytogenetic remission (≤35% Ph+metaphases), CCR complete cytogenetic remission, ALL acute lymphoblastic leukemia

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) [67]. 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 [32]. 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 [57].

Imatinib resistance

Several open questions remain, notably those concerning the development of imatinib resistance, which is rare in early chronic phase, but increases in frequency along the course of the disease [28, 39]. Essentially two mechanisms underlie the development of imatinib resistance:
  1. 1.

    Mutations of the ATP-binding site of the BCR-ABL tyrosine kinase domain

  2. 2.

    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 [40]. 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 [8], but cessation of imatinib therapy and alternative therapy with other drugs seem to be able to improve prognosis [40].

Several approaches appear feasible to prevent or overcome imatinib resistance:
  1. 1.

    To increase imatinib dosage to 600 or 800 mg

  2. 2.

    To combine imatinib with other drugs of known anti-CML activity

  3. 3.

    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 [82]. Kantarjian et al. [48] 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).

The first of these studies, the German CML Study IV, started recruitment in July 2002. The study compares imatinib monotherapy at 400 mg vs the combination of imatinib plus IFN (conventional or pegylated) vs imatinib plus low-dose ara-C vs imatinib after IFN failure (Fig. 4a). The sequential treatment concept of imatinib after IFN failure is supported by the modes of action of the two drugs. IFN has been shown to induce a T-cell response against myeloblastin, which is associated with complete cytogenetic remission [9]. No such response has been observed with imatinib that may even inhibit T-cell activation [12]. It therefore might well be that the sequential as compared to the simultaneous treatment approach provides an advantage. After imatinib failure, allogeneic stem cell transplantation is recommended for all patients who have a donor and can tolerate the procedure (Fig. 4b). All patients suitable for transplantation, but without a donor, will be used to compare outcomes after allografting and best available drug treatment. In patients above age 45, the feasibility and efficacy of reduced intensity conditioning [70] will be analyzed in a randomized fashion. This goal will hopefully contribute to better cost-effectivity.
Fig. 4

Study outline of CML Study IV. a Randomized comparison of imatinib vs imatinib in combination. b Evaluation of the role of allografting in the imatinib era including the randomized comparison of reduced-intensity conditioning vs age-adjusted standard conditioning in the elderly. Indications for allografting (according to transplantors of the German CML Study Group): high-risk patients (new score), low transplantation risk (Gratwohl score 0–1) and imatinib failure

By March 2005, 568 patients had been randomized. In a pilot phase, the feasibility of the protocol was analyzed. There were no unexpected events. The definitions of imatinib failure and transplantation indications in the imatinib era were adapted as shown in Table 2.
Table 2

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 [31])

Low transplantation risk (Gratwohl score 0–1 [30])

Imatinib failure

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.

New inhibitors

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 [79], PD166326 of Sloan-Kettering [85], AP23464 of Ariad Pharmaceuticals [69]), 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 [79].

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 [29]. 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 European Group for Blood and Marrow Transplantation (EBMT) score by Gratwohl et al. [30], has been prospectively confirmed [73]. It allows the recognition of patients with especially low or high transplantation risks (Fig. 5). Current management of newly diagnosed patients with CML therefore has to include the evaluation of patients according to risk profile and transplantation risk. The German CML Studies III and IIIA evaluate outcomes after allografting vs best available drug treatment according to risk profiles. The final evaluation of CML Study III is planned for 2005. An early simulation of possible outcomes of this study using IFN- or hydroxyurea-treated patients of CML Study I and a matched cohort of transplanted patients registered with the International Bone Marrow Transplant Registry (IBMTR) had shown that the transplantation benefit is best for high-risk patients and the least certain for low-risk patients [23]. In the simulation, no survival benefit could be ascertained after an observation period of 8 years. It appears possible that with improvements in drug therapy (imatinib) a benefit for transplantation may be observed in non-high-risk patients even later, in spite of improvements in transplantation procedures and management of graft versus host disease complications. Currently, transplantation indications are reconsidered in view of the increasingly recognized risk of imatinib resistance.
Fig. 5

Gratwohl score. Donor type (HLA identical sibling score 0, matched unrelated donor score (1), disease stage (first chronic phase 0, accelerated phase 1, blast crisis (2), age of recipient (<20 years, 0; 20–40 years, 1; >40 years, 2), gender combination (all, except next, 0; male recipient/female donor, 1), time diagnosis to transplant (<12 months, 0; >12 months, 1).A score of 0 designates the lowest, a score of 7 the highest risk

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 [70] 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 [26] 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 [44].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.

Targeted therapy comprises mainly two classes of agents: small molecule inhibitors (mostly of tyrosine kinases) and monoclonal antibodies. Examples of these two classes of agents, their target structures and cancers treated with these agents are presented in Table 3.
Table 3

Examples of targeted therapies in clinical oncology






Imatinib (Glivec), AMN107, BMS354825, AAP23464


Advanced NSCLC

Gefitinib (Iressa)

Erlotinib (Tarceve)



Trastuzumab (Herceptin)



Bevacizumab (Avastin)


Metastic CRC

Cetuximab (Erbitux)



Bevacizumab (Avastin)


Metastic breast cancer

Transtuzumab (Herceptin)



Erlotinib (Tarceva)


Locally advanced head and neck cancer

Anti-EGFR-MAB h-R3


Cetuximab (Erbitux)


Pancreatic cancer

Erlotinib (Tarceva)



Trastuzumab (Herceptin)


Renal cell cancer

Bevacizumab (Avastin)





Multiple myeloma

Bortezomib (Velcade)

mTOR kinase

CML, GIST, breast–lung cancer (in combination)

Rapamycin, CCI-779 Everolimus (RAD001, Certican)

Farnesyl transferase/ras pathway

CML, lung cancer, breast cancer

Tipifarnib (Zarnestra)

Lonafarnib (Sarasar)


Head and neck cancer

Celecoxib (Celebrex)

Colorectal cancer

NSCLC non-small cell lung carcinoma, CRC colorectal 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% [76]). 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 [36]. 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 [83]. 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.

In summary, the treatment of choice in chronic phase CML is now imatinib, with IFN ± hydroxyurea a reasonable alternative; see algorithm in Fig. 6. Residual disease even after successful treatment with imatinib and the evolving imatinib resistance argue against a curative potential of imatinib alone. Combinations of imatinib with other effective anti-CML drugs might improve outcome. The new more potent tyrosine kinase inhibitors with efficacy also in imatinib resistance offer new perspectives. At present, the only treatment option with generally accepted curative potential continues to be allografting. The evaluation of the patient’s risk profile and transplantation risk becomes increasingly important for counseling patients with regard to the best treatment option. The prognosis in blast crisis remains poor, and a better understanding of the mechanism of its evolution is urgently needed. The success with targeted therapy in CML has led to an intensive search for targets and inhibitors also in other cancers.
Fig. 6

Treatment algorithm CML 2005

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Rüdiger Hehlmann
    • 1
  • Ute Berger
    • 1
  • Andreas Hochhaus
    • 1
  1. 1.III. Medizinische UniversitätsklinikFakultät für Klinische Medizin Mannheim der Universität HeidelbergMannheimGermany

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