CML Anak

ChronicMyeloid
MyeloidLeukemia
Leukemia—
—
Chronic
Advances
Advances
inBiology
Biologyand
andNew
NewApproaches
Approaches
in
toTreatment
Treatment
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Graft-Versus-Leukemia
Effect
The eradication of leukemia by
allogeneic stem-cell transplantation
does not depend entirely on the
chemotherapy and radiotherapy given
during the conditioning phase that
precedes stem-cell infusion, but that it
relies also on an ill defined graftversus-leukemia effect.

Graft-Versus-Leukemia
Effect
Mediated by allogeneic T cells, 4 discrete lines of evidence:
1.The incidence of relapse in leukemia is inversely related
to the incidence of GVHD
2.Relapse is more common after the transplantation of
hematopoietic stem cells from syngeneic rather than
allogeneic sibling donors
3.Depletion of T cells from the donor inoculum greatly
increases the risk of relapse
4.The infusion of lymphocytes collected from the original
donor can restore complete remission in a patient who
has had a relapse after allografting, especially in the case
of CML.

Treatment Options
1. Alternatives to Transplantation
Cytotoxic T lymphocytes directed
against known antigens could prove
valuable in treating minimal residual
disease but may not be so effective
in dealing with large quantities of
leukemia.

Imatinib → interferon alfa as best
single agent for treating CML in the
chronic phase in patients who were not
eligible
for
allogeneic
stem-cell
transplantation.
The conclusion that imatinib prolongs
the survival of patients treated in the
chronic phase of disease has been
unproved for the present.

• Food and Drug Administration →
multicenter study with imatinib
• Although resistance to imatinib as a
single agent seems to be rare in
patients treated in the chronic phase
of disease, resistance does eventually
develop in the majority of patients
treated in the advanced phase.

• Studies in vitro of resistant cell lines have
shown amplification of the BCR-ABL gene
in association with overexpression of the
oncoprotein
• Resistant patients to imatinib →
had
mutations in the ABL kinase domain →
specific amino acid substitutions → kinase
accepting ATP → phosphorylating (the
substrates that generate the CML
phenotype).

• The resistant phenotype is probably
due to the capacity of CML cells
to recruit signal-transduction
pathways that bypass the block or,
by in vitro mutagenesis, to point
mutations outside the kinase
domain

Treatment Options
2. Stem-Cell Transplantation
It is now generally accepted that
allogeneic
hematopoietic
stem-cell
transplantation can cure CML in
selected
patients,
but
stem-cell
transplantation is still associated with
an appreciable risk of complications
and death, due principally to GVHD and
opportunistic infections.

Factors that influence the risk of transplantation related
death are:
 patient’s age,
 the phase of disease
 the duration of disease
 the degree of donor–recipient histocompatibility
 the donor’s sex
→ a young patient with CML in the chronic phase who
has an HLA-identical sibling donor can expect to fare
much better after transplantation than an older patient
with accelerated-phase disease who has a less well
matched, unrelated donor.

Graft-versus-leukemia effect plays a major part
in the eradication of CML → Reductions in the
dose of cytotoxic drugs and maximize the
number of hematopoietic stem cells and
lymphocytes transfused to the patient in
pretransplantation conditioning regimen.
By reducing the intensity of conditioning in this
way,
it
may
be
possible
to
offer
transplantation to patients who would not
otherwise be eligible because of older age or
the presence of concomitant disease.

Longterm treatment with imatinib and
transplantation would be to offer patients
with newly diagnosed CML, though neither
both results can be accurately predicted.
The best approach to managing CML in
young patients who have a suitable
transplant donor may be clearer in one or
two years, when we have gained more
experience in the use of imatinib.

Therapeutic Terms
Need to define the true clinical potential
of imatinib and to ascertain whether
combining this agent with other signaltransduction inhibitors, other cytotoxic
drugs, or differentiating agents can improve
its efficacy.
Need to know whether immunizing
patients with CML can prolong their survival
or contribute to the eradication of disease →
those will be solved within the next 5 years.