Not so long ago, therapeutic decisionsin chronic myeloid leukemia(CML) were ratherstraightforward: Allogeneic bonemarrow transplantation was performedin all patients with a donorwho were deemed fit enough for theprocedure, interferon-alfa was administeredto all others able to tolerate it,and the remainder received hydroxyurea.The advent of imatinibmesylate (Gleevec) and, to a lesserdegree, the development of reducedintensityconditioning regimens, haveradically changed the approach totreating CML and have considerablyincreased the complexity of treatmentdecisions.
Not so long ago, therapeutic decisionsin chronic myeloid leukemia(CML) were ratherstraightforward: Allogeneic bonemarrow transplantation was performedin all patients with a donorwho were deemed fit enough for theprocedure, interferon-alfa was administeredto all others able to tolerate it,and the remainder received hydroxyurea.The advent of imatinibmesylate (Gleevec) and, to a lesserdegree, the development of reducedintensityconditioning regimens, haveradically changed the approach totreating CML and have considerablyincreased the complexity of treatmentdecisions.Biology of CML: Unsolved Issues
In the first part of their paper,Mughal and Goldman briefly reviewsome aspects of the biology of CML.A few issues need to be clarified. Bcr-Abl-negative CML is clearly a mixedbag. However, it should be noted thatthe diseases associated with activationof platelet-derived growth factorreceptor-beta or fibroblast growth factorreceptor type 1 have clinical features-such as eosinophilia andmonocytosis-that are not typical of"standard" CML. Although thereis certainly overlap with Bcr-Abl inthe use of signaling pathways, majordifferences exist. Not surprisingly, thetranscriptional profile of Bcr-Abl-transformed hematopoietic cells is distinctfrom that of platelet-derivedgrowth factor receptor-beta-transformedcells.The authors comment that we stilldo not understand "precisely how[Bcr-Abl] induces the leukemic phenotype."Although this is true, I wouldargue that it may be time to acknowledgethat the transforming networkoperated by CML is imprecise by itsvery nature, exhibits extensive redundancy,and is partially driven by stochasticrather than linear processes. Incontrast, we have little knowledge aboutthe mechanisms responsible for diseaseprogression. None of the geneticlesions associated with blast crisis, exceptrearrangements affecting the EVI-1transcription factor, explain the moststriking feature of blast crisis, which isthe loss of terminal differentiation. Improvingour understanding of diseaseprogression appears crucial, as onecould argue that CML would not posemuch of a clinical problem if it remainedin chronic phase.Treatment Decisions in CML
The larger part of the article nicelyreviews the treatment of CML, includingimatinib and allogeneic stem celltransplantation. Therapy for CML is amoving target, as the follow-up of patientson imatinib is relatively short,and no direct comparison has beenmade between conventional and reduced-intensity conditioning regimens.Thus, current recommendations have alimited half-life. At the heart of thedilemma is the question of whether imatinibwill eventually replace or onlydelay allogeneic transplantation. To putthis into perspective, one needs to considerthe obvious short-, likely medium-,and potential long-term problemsassociated with imatinib therapy.In the short term, resistance to imatinibafter an initial response is thekey issue. Although the risk of resistanceis much higher in patients withadvanced disease, I somewhat disagreewith the authors' notion that itis rare in chronic phase. In phase IIand III trials in chronic phase CMLpatients after failure of interferon-alfaas well as in newly diagnosed patients,the rates of disease progressionwere 20% and 12% at 40 and 31months, respectively.[4,5] Undoubtedly,these results are an enormousimprovement over those achieved withinterferon-based therapy. Given that5-year survival rates in selected patientsafter allografting approach 75%in some studies,[6,7] this rate of relapseis nonetheless significant.Another important point is that responsesinduced by dose escalationfor resistant disease are frequently notdurable. For optimal managementof resistant patients, it will be crucialto determine the specific mechanismof resistance and tailor therapy accordingly.Illustrations of this paradigminclude the differentialsensitivity of various Abl kinase domainmutants to higher doses of imatinib or to second-generation Ablinhibitors. Without mutationalanalysis, rational therapy of such patientswill be impossible.Arguably better than treating relapsewould be to avoid it in the firstplace. At present, it is unknown whetherdisease eradication (defined as neg-ativity by reverse transcription- polymerasechain reaction) is required toavoid relapse or if "operational" curemay be achieved, as discussed byMughal and Goldman. Given thatnewly diagnosed patients with a morethan 3-log reduction of Bcr-AblmRNA have excellent progressionfreesurvival despite the presence ofminimal residual disease, one wouldhope for the latter. Experiencewith other malignancies however suggeststhat disease persistence, even ata low level, indicates a continuousrisk of relapse. Thus, disease persistenceis likely to become the key issuein the medium term.Several large studies are under wayin Europe that are testing combinationsof imatinib with interferon-alfa or cytarabine,as well as high-dose imatinibvs the standard dose, and molecularremission will be a critical end point.The rationale for these combinations isbased on in vitro observations in celllines or committed CML progenitorcells that do not necessarily apply tocells that cause persistence in vivo.Thus, efforts need to be directed towardunderstanding the mechanismsunderlying imatinib's failure to eradicateresidual disease, so that rationaltherapeutic strategies can be developed.Lastly, in the long term, side effectsmay still become a relevant issue. Generally,imatinib is well tolerated, withminimal toxicity. That said, the perspectivesmight change if patients aretreated for many years, perhaps decades.Examples include the recentlyreported effects of imatinib on testosteronemetabolism with some mendeveloping gynecomastia or lateoccurringliver toxicity. As withpersistent disease, the key to solvingthis problem is disease eradication.However, even after the last CML cellis eradicated, the bone marrow maynot become normal, as clonal chromosomalabnormalities, sometimes associatedwith a myelodysplastic syndrome,have been seen in patients witha cytogenetic response.Advising the NewlyDiagnosed Patient
Patients in accelerated phase or blastcrisis CML should be offered an allo-geneic transplant, with imatinib usedfor tumor reduction, as responses inadvanced disease are generally not durable.For chronic phase patients,Mughal and Goldman outline two approaches.One calls for a trial of imatinibin all patients, reserving transplantfor those who fail to respond optimallyor become resistant. In the short term,this strategy will preserve a span ofhigh-quality lifetime, as the early mortalityafter allografting is avoided. Overthe long term, additional factors willbecome relevant.Much depends on the question ofwhether imatinib treatment may compromisea subsequent allograft. Theavailable retrospective data are controversial,and the cohorts investigatedare high risk, potentially obscuringdetrimental effects.[15,16] Prospectivestudies in standard-risk patients areneeded to clarify this crucial issue. Anotherimportant point is that the approachrequires high-quality follow-upto detect resistance as early as possible.The relative lack of side effects and theease of administration of imatinib maylead to less stringent follow-up outsideof studies and major centers.The second approach outlined bythe authors is to offer allografting topatients with a low risk of transplantrelatedmortality. Luckily, our abilityto identify such patients has improvedconsiderably, although much of thedata must be re-validated in patientstransplanted with reduced-intensityconditioning regimens.Conclusions
With the many uncertainties describedabove, either approach is defendableat present. One additionalconsideration appears crucial: Thepatient's personal preference is a majorfactor in the decision-making process,particularly in equivocalsituations, and thanks to the Internet,patients are much better informed todaythan they were not so long ago.
The author has no significantfinancial interest or other relationshipwith the manufacturers of any products or providersof any service mentioned in this article.
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