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CML in general

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#1 valiantchong


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Posted 05 May 2011 - 11:36 AM

Chronic myelogenous leukaemia (CML)

Clinics and Pathology

DiseaseCML is a malignant chronic myeloproliferative disorder (MPD) of the hematopoietic stem cell.
Phenotype / cell stem originEvidence exists for the involvement of the most primitive and quiescent hematopoietic stem cell compartiment (CD34+/CD38-, Thy1+): t(9;22) is found in myeloid progenitor and in B-lymphocytes progenitors, but, involvement of the T-cell lineage is extremely rare. The existence of a highly quiescent stem cell population has been demonstrated in patients with CML. More recently, the presence of Ph chromosome has been demonstrated in vascular endothelium of CML patients at diagnosis. Ph+ stem cells with stem markers of endothelial cells have been shown to be present at the level of single stem cells. These findings have suggested that a putative "hemangioblast" giving rise to both hematopoietic and endothelial cells could be present on adult marrow and be a target of t(9;22) translocation.
EpidemiologyAnnual incidence: 10/106 (from 1/106 in childhood to 30/106 after 60 yrs);
median age: 30-60 yrs;
sex ratio: 1.2M/1F.
ClinicsThe disease is currently discovered after a routine blood count revealing hyperleucocytosis and circulating immature white blood cells. A splenomegaly might be present. Bone marrow aspirate with cytogenetic analysis is required, as well as molecular evaluation for the detection of BCR-ABL oncogene which is quantified by calculating BCR-ABL / ABL ratio. The disease is classified most commonly using Sokal or Hasford scores. The natural history of the disease including classically three phases (Chronic phase, accelerated phase and blast crisis) has been profoundly modified by the current therapy regimens using tyrosine kinase inhibitors. For instance, recent update of the IRIS study demonstrates the progressive reduction of secondary events over time with no blast crisis occurring after 6 years. Most patients now seen in accelerated phase or in blastic phase are those who relapse after IM and/or dasatinib/Nilotinib therapies. The major problems in CML are the resistance encountered as first line therapy as well as intolerance to TKI therapy leading to discontinuation of the drugs. In the IRIS trial, approximately 30% of patients discontinue imatinib for reasons of resistance (15%) or intolerance. Finally, it is clear that currently available TKI therapies do not eradicate the most primitive stem cells, explaining relapses occurring after discontinuation of treatment (see below).
CytologyHyperplastic bone marrow; myeloid proliferation with maturation; some myelodysplastic features can be seen on Imatinib therapy after disappearance of the Ph clone. The significance of these abnormalities is not known but very rare patients evolve into myelodysplastic or leukemic phase. The typical AL cytology can be seen when patients evolve into accelerated or blast phase (see: t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL).
TreatmentThe treatment of CML has been revolutionized by the introduction of targeted therapies to the clinical practice. The first of these drugs was imatinib mesylate (IM) targeting the tyrosine kinase activity of BCR-ABL. In a large international multi-center trial, the use of IM as a first line therapy has been compared to standard IFN-ARA-C regimen (IRIS trial). This trial has clealy shown the advantages of IM in terms of complete haematological response, (CHR) complete cytogenetic response (CCR) and molecular response (MR) as compared to IFN-ARA-C regimen. Interestingly, the outcome on IM therapy has been shown to be correlate with the Sokal score at diagnosis. The most recent update of this trial has shown for the first time, a reduction of secondary events (accelerated phase, blast crisis) over time, with no patients progressing towards blast crisis after 6 years of therapy. However, several questions remain to be solved before demonstration of a "cure" under IM therapy: 1-The attempts to interrupt IM therapy has been followed in most cases by a cytogenetic and haematological relapse; 2-The most primitive stem cells seem to be resistant to IM therapy at least in vitro ; 3-The resistance to IM-therapy has been found to be associated, especially in patients who received it as second line treatment, with the occurrence of mutations in the ABL-kinase domain, impeding the binding of the drug to its target. Some of these mutations, occurring in the P-loop or in the ATP binding pocket ("gatekeeper" mutation T315I ) lead to a total resistance to IM; requiring the interruption of the drug. If the mutations reside outside these regions (C-lobe of the SH1 kinase domain), the increase of IM dose could lead to molecular responses. Detection of ABL-kinase mutations has therefore become a clinically useful molecular test. The majority of ABL-kinase mutations other than T315I have been shown to be targetable by second generation of TK inhibitors, essentially Dasatinib (Sprycell) and Nilotinib (Tasigna). Dasatinib is a combined SRC and ABL-inhibitor which is indicated as a second line therapy in CML patients failing on IM therapy or intolerant to IM-therapy. Nilotinib is a TK inhibitor with high affinity for ABL-tyrosine kinase. Novel therapies to eliminate the stem cells with T315I mutation remain a major futur challenge.
PrognosisTKI therapies have changed the prognosis of CML as well as the natural history of the disease. Results from the IRIS trial suggest that the majority of patients with CML at first chronic phase will attain complete cytogenetic and major molecular responses with however persistence of minimal residual leukemic stem cells. Although it is difficult to qualify CML as an indolent disease, the estimated median survival with the available therapies is 25 years.

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