7/31/2019 CML Was Once Considered an Incurable Disease

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7/31/2019 CML Was Once Considered an Incurable Disease

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chromosome positive metaphases in the marrow. A reduction of Ph positive cells to less than 35% was seen

in 30-50% of patients, and complete cytogenetic responses were found in 10-20%. This group of patients

gained the greatest survival advantage, and had a median survival of more than 8 years. Up to 20% of

patients tolerated interferon-alpha poorly, and could not continue the treatment. A disadvantage to

interferon-alpha treatment was that it may compromise the outcome of subsequent allogeneic SCT, owing

to an increase in GvHD.

Imatinib is a relatively specific inhibitor of the BCR-ABL tyrosine kinase, which was approved for the

treatment of CML in 2002. BCR-ABL normally places phosphate groups on other proteins, which serve to

activate them. These proteins, in turn, activate downstream proteins, creating an expanding cascade of

protein activation that ultimately results in uncontrolled growth. To activate these downstream proteins,

BCR-ABL requires adenosine triphosphate (ATP), which donates the phosphate group. Imatinib functions by

competing with adenosine triphosphate (ATP) for binding to the BCR-ABL tyrosine kinase. If the ATP binding

site is occupied, then ATP cannot donate the phosphate and BCR-ABL can no longer activate downstream

signalling proteins that promote cell division. Disease progression is essentially stopped by blocking this 1

ATP binding site, meaning that BCR-ABL is not able to activate downstream effector tyrosine kinase

molecules that drive WBC proliferation. The 7 year update on the IRIS study of imatinib treatment

confirmed the efficacy of imatinib in chronic phase CML and the durability of response. At the 7 year mark,

93% of the imatinib treated patients had not progressed to accelerated phase or blast crisis, and 73% had

not lost complete cytogenetic response. The achievement of a major cytogenetic response was associated

with a statistically significant improvement in overall survival.

Prior to imatinib, allogeneic stem cell transplant was a good treatment option. Currently allogeneic stem cell

transplant remains an important therapy in certain circumstances, for example imatinib resistance, or

patients in accelerated phase or blast crisis, and those with T3151 mutations. The German CML study group

recently reported a surprisingly good survival rate of imatinib-resistant chronic phase patients undergoing

allogeneic stem cell transplant. Allogeneic stem cell transplantation remains the only proven cure for CML.

Stem cells used for allogeneic transplantation can be obtained from either the bone marrow, or the

peripheral blood of the donor. The toxicities associated with this technique are formidable. Patients are at

risk for bleeding complications and infectious complications during the 2- to 3-week peritransplant period

when their blood counts are very low before bone marrow recovery (engraftment). After engraftment,

patients are at risk for GVHD, in which the donor bone marrow produces alloreactive T-cells from the donor,

which attack the recipients tissues. Common organs affected by GVHD include the skin, gastrointestinal (GI)

tract, and liver. Grade 3 or grade 4 GVHD associated with the liver or the GI tract is associated with mortality

approaching 100%.

ABL inhibitors such as nilotinib and dasatinib can overcome resistance caused by some, but not all BCR-ABL

mutations. Very recently allosteric inhibitors of ABL have been identified, which bind outside the catalytic

site. The latter molecules bind to the myristate binding site of ABL, rather than the ATP binding site targeted

by imatinib. This action induces a change in the catalytic domain of the kinase and this in turn inhibits the

enzyme activity of ABL. When combined with imatinib, an ABL allosteric inhibitor can overcome resistance

caused by BCR-ABL mutations such as T3151, which illustrates the benefit of combining different modes of

inhibition on the same target.

CML is one of the few malignant diseases triggered by a single oncogene (bcr-abl). This is the reason for the

excellent efficacy of molecularly targeted CML therapy. Unfortunately, evidence is accumulating that

residual leukemia may persist even in the best responders and that therapies directed at the BCR-ABL

tyrosine kinase are not curative since they fail to eradicate the CML stem cells. Thus, the CML saga

continues, and much work remains to be done.