CMLNews: Dr. Kim, warm thanks to
you for taking the time to update worldwide
CML patients and caregivers on
the new CML drug trials in our online
CML Support Group, AsianCMLSupport.
You have conducted the Sprycel
trials and are conducting the Tasigna
trials in Korea. Are these two new
kinase inhibitors showing promise in
treating resistant CML?
Dr. Kim: Both Sprycel and Tasigna
have demonstrated encouraging responses
and will become very promising
agents for most of the resistant CML
clones except T315I or some other mutant
clones.
CMLNews: How many patients participated
in the Sprycel trials and what were
the response rates in your trials?
Dr. Kim: At St. Mary’s Hospital, the Catholic University of
Korea, 64 imatinib-resistant or intolerant CML patients participated
from March 2005 to March 2006 for the Sprycel phase II
study. The median follow-up duration of treatment was 11
months. Among them, 57 (57/64; 89%) patients achieved major
hematologic response (MHR; CHR and NEL), and MCyR
was seen in 34 (34/64; 53%) patients. Among 34 patients with
MCyR, 25 (39% of the cohort) patients showed CCyR. As
Sprycel comes to market as a kind of frontline therapeutic
agent, the most encouraging sign is that the better responses
were achieved in less advanced patients i.e., all 30 chronic
phase CML patients achieved MHR (21 in CHR and 9 in NEL)
and 70% (21/30) achieved MCyR with 53% of the patients in
CCyR (16/30 patients). In 34 advanced CML patients, 79%
and 32% achieved MHR and MCyR respectively (27/34 MHR
and 11/34 MCyR).
CMLNews: What were the major side-effects encountered by
patients on Sprycel?
Dr. Kim: Greater than Grade 3 major side-effects were hematologic toxicities, such as neutropenia
and thrombocytopenia. 46 of 64 (71%) patients had Grade 3 thrombocytopenia,
and Grade 3 neutropenia was observed in 43 of 64 (67%) patients. As hematologic toxicities are
closely related to therapeutic effect of target-oriented inhibitors
such as Gleevec, Sprycel and Tasigna, cytopenia (low
counts) may not be an important toxicity in early-stage
disease. Non-hematologic toxicities were relatively less
and more manageable in most patients. Grades 3 and 4
non-hematologic side-effects related directly to Sprycel
were gastrointestinal bleeding in 3 of 64 patients;
nausea/vomiting in 3; diarrhea in 2; neutropenic fever in 2;
and 2 pleural effusions. Other side effects were skin rash,
headache, general edema, anorexia, weight loss, and
pneumonia. Pleural effusion was a particular problem
during Sprycel trials as 14 patients developed pleural
effusion (all grades). Overall toxicities during Sprycel
trials were less and manageable compared to Gleevec trials.
Also, side-effects were less in chronic phase resistant
patients compared to advanced phases.
CMLNews: What percentage of patients developed the T315I
mutation on Sprycel? What are the therapy options for
patients developing the T315I mutation?
Dr. Kim: A total of 11 patients in our Sprycel trial developed
the T315I mutation. Among them, 6 patients already had
T315I mutation before Sprycel treatment, and T315I mutant
clones emerged in 5 patients (7.8%) during Sprycel treatment.
At present, we think T315I mutant clones have been selected
and expanded by more potent second-generation kinase inhibitors.
We have treated 9 patients with escalated dosage of
daily 180mg or 200mg. Although 5 patients showed transient
hematologic response, now only 3 patients are still on Sprycel
treatment. Although we have tried to do allografting for all
T315I patients, some patients were not eligible for allografting
due to no HLA-matched donor in the family and unrelated
donor banks, poor economic status, serious concomitant complications,
or old age. Based on this result, early allografting should be
recommended for patients having the
T315I mutation. Otherwise, we may
wait for upcoming phase II trial of the
third-generation inhibitors such as
VX-680, an aurora kinase inhibitor, or the SGX series.
CMLNews: Is mutations testing for
ABL point mutations done in Korea?
Dr. Kim: Of course, we are conducting
mutational assays to verify the type
of resistance in Glivec-failure patients. As we published in
the Journal, Haematologica (Haematologica, 2006 May;
91:659-662), both ASO-PCR and direct sequencing assays
have been simultaneously used in my laboratory, which is one
of the 4 referral labs for PCR and mutation assay worldwide.
According to our observation, among the 68 Glivec-resistant
CML patients studied, various Abl mutations were detected in
44 patients (65%) and the most common type was the T315I
mutation (13/44; 29.5% ).
CMLNews: Were there any other ABL point mutations not
overcome by Sprycel?
Dr. Kim: The T315I mutation showed strong resistance to
Sprycel. In addition, the F317L mutation also demonstrated
transient hematologic response to Sprycel in my three cases.
According to other studies presented in 2005 ASCO, E255V,
F359V, M388L and H396R mutations also showed relative
resistance to Sprycel in clinical trials.
CMLNews: When is Sprycel likely to be marketed in Korea?
Dr. Kim: Since the Korean study group joined the Sprycel
global phase II trial at the same time with the US and
French teams, I am expecting an approval from Korean
FDA within this year. However, the most important issue
for availability in market may be whether the cost of Sprycel
will be covered by the National Insurance Program of
the Korean government. In general, insurance coverage
may be possible after the middle of next year.
CMLNews: How many patients do you have in the Tasigna
trials and what are the remission rates?
Dr. Kim: In the Tasigna phase II study at my hospital, a
total of 11 imatinib-resistant or intolerant CML patients
have participated from September 2005 to date, and the
median follow-up duration of treatment is 7 months.
Among them, patients achieving major hematologic response
(MHR; CHR and NEL) were 9 (9/11; 82%) patients, and MCyR
were in 5 (5/11; 45%) patients. Among 5 patients who achieved
MCyR, 2 (18%) patients showed CCyR. In comparison to Sprycel,
Tasigna showed a better response in less advanced disease, i.e. all of
3 chronic phase CML patients achieved a CHR and 67% (2/3)
achieved MCyR (1 in CCyR). In 8
advanced CML patients, MHR
showed in 6 (75%), and 3 patients
(38%) were in MCyR.
CMLNews: What are the major side-effects on Tasigna?
Dr. Kim: In the Tasigna study, the major side-effects were
hematologic toxicities. A neutropenia or thrombocytopenia
more than Grade 3 was seen in 8 of 11 (73%) patients. In
non-hematologic toxicities, a few patients showed over
Grade 3 toxicities of vomiting, elevation of liver enzymes,
hyperbilirubinemia, diarrhea, and neutropenic fever.
CMLNews: Did any patient develop the T315I mutation on
Tasigna?
Dr. Kim: No. One patient already had T315I mutation
before Tasigna treatment and the response was not good.
During Tasigna trials, no patient developed the T315I mutation.
CMLNews: Between the two drugs, which is the better drug, in
your opinion, in terms of response and side-effects?
Dr. Kim: Sprycel has been demonstrating the better hematologic
and cytogenetic responses. However, in terms of sideeffect,
Tasigna is a relatively safer drug than Sprycel. From
these points of view, both Sprycel and Tasigna will be
promising drugs for the control of CML in the future. Optimization
of various therapeutic strategies using these two potent second-
generation tyrosine kinase inhibitors might be an important
issue of future therapy.
CMLNews: In the Sprycel and Tasigna trials, how have advanced
phase patients fared? Were there many relapses in accelerated
phase and blast crisis?
Dr. Kim: As I mentioned before, in advanced phases, response
rate was lower and response duration was relatively shorter than
in chronic phase. From this observation, we know early therapy
with Sprycel and/or Tasigna is important to get a better response,
and a frontline therapy in newly diagnosed chronic
phase CML should be applied earlier.
CMLNews: Dr. Kim, you are a transplant specialist. What is
the role of allogeneic transplant in today’s times?
Dr. Kim: Not so long ago, almost all CML specialists were
transplant-oriented physicians. However, most of the experts
have been turning into drug therapy specialists. This change has
been caused by the fascinating effect of Glivec, Sprycel, and
Tasigna, and a recent doubt about curability by allograft. Now
the role of transplantation in CML is very limited. We can consider
an allograft only in very young patients less than 30 years
with HLA matched sibling donors, advanced phase patients at
diagnosis, poor or suboptimal responders to Glivec, Sprycel, and
Tasigna, and patients having a mutation such as T315I.
CMLNews: Gleevec is a great drug, bringing remission to the
majority. However, it has not been able to eradicate residual
disease in most CML patients and we have to take the drug
long-term. What are your thoughts on a CML drug cure?
Dr. Kim: Of course, neither Glivec, Sprycel nor Tasigna
may be curable modalities. However, various combination
therapies using Glivec, Sprycel and Tasigna might
approach CML curability. If we successfully control T315I
mutant clone with 3rd generation kinase inhibitors developing
now, a combination of Sprycel + Tasigna + T315I mutant
inhibitors + CML vaccine will open a new era of CML
cure with drug therapy only.
CML News: Prof. Kim, there are patients in CCR with
Gleevec but not in 3-log reduction. Patients are interested
in knowing the advice of CML experts like yourself
whether it is reasonable to switch to the new drugs like
Sprycel and Tasigna to try to achieve MMR and PCRU?
Dr. Kim: Of course Sprycel and Tasigna will be promising
options in these cases. Gleevec dose escalation
with frequent monitoring plan will be best at present.
Nilotinib and Dasatinib trials for suboptimal cytogenetic
and molecular responders will start shortly within this year.
| Dr. Dong-Wook Kim, MD. PhD Professor, Division of Hematology, St. Mary’s Hospital, The Catholic University of Korea; Director, Molecular Genetic Research Laboratoy, Catholic Medical Science Institute, The Catholic University of Korea; Director, Asia-Pacific Central Referral Laboratory of Novartis Global Clinical Trials Principle Investigator of the Phase I/II/III Imatinib trials in Korea Principle Investigator of the Phase II/III Nilotinib trials in Korea Principle Investigator of the Phase II/III Dasatinib trials in Korea was interviewed by CMLNews, the Asian CML Support Group Newsletter. Interview conducted: September, 2006 |