The development of the targeted
anticancer medicine imatinib has been a landmark event in the treatment of
patients with chronic myeloid leukemia (CML), a cancer of the bone marrow.
However, over time, the cancer can become resistant to this treatment,
usually because of mutations in the protein that imatinib targets. Two
studies being presented today at the 48th Annual Meeting of the American
Society of Hematology (ASH(TM)) highlight new compounds in development that
can effectively treat CML when imatinib is no longer effective.
“This is important progress for patients who relapse on imatinib
therapy,” said Charles A. Linker, MD, University of California, San
Francisco. “Not only does this research show the efficacy of new treatments
for imatinib- resistant disease, it also demonstrates the value of looking
at each patient’s mutation pattern to determine an individual course of
therapy.”
Hematologic and Cytogenetic Response Dynamics to Nilotinib (AMN 107)
Depend on the Type of BCR-ABL Mutations in Patients with Chronic
Myelogenous Leukemia (CML) after Imatinib Failure [Abstract #749]
Treatment with imatinib has allowed patients with chronic myelogenous
leukemia (CML) to experience a nearly 90 percent five-year survival rate,
as the drug blocks the tyrosine kinase BCR-ABL, an abnormal protein driving
the overproduction of abnormal white blood cells characteristic of
leukemia. However, many patients have eventually developed resistance to
this treatment because their cancer cells are able to mutate and adapt,
causing their disease to relapse.
Researchers studied nilotinib, a novel treatment that blocks the
BCR-ABL protein, to determine its effectiveness among patients for whom
imatinib has stopped working. In vitro work showed effectiveness even in
patients developing BCR-ABL mutations associated with resistance to
imatinib. Investigators looked at blood samples from 101 CML patients, 64
of whom were in the early or chronic phase, 22 in the later or accelerated
phase, and 15 in the final or blast crisis phase of the disease, and
screened for the BCR-ABL gene mutation that signals CML.
Prior to treatment with nilotinib, researchers found 28 different
BCR-ABL mutations in 61 patients. Of this group, nine showed two mutations,
three showed three mutations, and one patient showed four mutations. When
treated with nilotinib twice a day (400 mg), 70 percent of patients with
mutations experienced a hematologic response, with the highest rate of
response seen in patients in the chronic phase (78 percent), followed by
accelerated phase (75 percent) and blast crisis (25 percent). Patients
without mutations responded even better to the therapy, as 88 percent
experienced a hematologic response rate.
Chronic phase patients whose genetic mutations had shown sensitivity to
nilotinib in the lab achieved a complete cytogenetic response within three
to six months. Two patients with the BCR-ABL mutation T315I — a mutation
highly resistant to both imatinib and nilotinib in the lab — showed no
signs of relapse of disease after one month and 11 months of treatment with
nilotinib, respectively.
“This preliminary data suggests that nilotinib may help patients for
whom imatinib has stopped working by overcoming the gene mutations that
cause imatinib resistance,” said Andreas Hochhaus, MD, of the Medical
Faculty Mannheim of the University of Heidelberg, Germany. “It also shows
the importance of determining each patient’s specific gene mutation, to
apply individualized dosage of nilotinib according to the mutation
pattern.”
Response to Dasatinib after Imatinib Failure According to Type of
Preexisting BCR-ABL Mutations [Abstract #748]
Dasatinib blocks the production of BCR-ABL and it has been shown to
treat CML and ALL that have become resistant to the standard therapy of
imatinib.
This study looked at the type of gene mutations that are more
responsive to treatment with dasatinib to confirm the best targets for
future therapy. Blood samples from 394 patients being treated with
dasatinib (198 chronic phase, 78 accelerated phase, 53 myeloid blast
crisis, and 65 lymphoid blast crisis/ALL) were monitored in three month
intervals to determine how the preexisting genetic mutations responded to
the therapy and if new mutations emerged. Prior to treatment, 46 different
BCR-ABL mutations were detected in 202 patients — 162 patients showed one,
33 patients showed two, six patients showed three, and one patient showed
four mutations.
Patients with mutations responded well to therapy, as complete
hematologic response was achieved in 91 percent of chronic phase patients,
62 percent of accelerated phase patients, 41 percent of myeloid blast
crisis patients, and 34 percent of lymphoid blast crisis/ALL patients.
Complete cytogenetic responses were similar and occurred in 37 percent of
chronic phase patients, 27 percent of accelerated phase patients, 28
percent of myeloid blast crisis patients, and 51 percent of lymphoid blast
crisis patients.
Researchers observed two response patterns in studying treatment with
dasatinib: some patients experienced a decrease in the BCR-ABL expression
and the proportion of the mutated clone simultaneously, while others
experienced a decrease in BCR-ABL followed by a decrease of the mutated
clone after a delay of four to six months. Five patients developed new
mutations associated with resistance to dasatinib, including T315I. The
T315I mutation is highly resistant to both imatinib and dasatinib.
“Dasatinib is an excellent treatment option for patients who have
become resistant to imatinib,” said lead researcher, Martin C. Muller, MD,
Medical Faculty Mannheim of the University of Heidelberg, Germany.
“However, we noted that response depended heavily on the type of genetic
mutation, which may signal a method for individualizing each patient’s
dose.”
The American Society of Hematology (hematology) is the
world’s largest professional society concerned with the causes and
treatment of blood disorders. Its mission is to further the understanding,
diagnosis, treatment, and prevention of disorders affecting blood, bone
marrow, and the immunologic, hemostatic, and vascular systems, by promoting
research, clinical care, education, training, and advocacy in hematology.
American Society of Hematology
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