CML Treatment- Management And Future Directions
Interview conducted after ASH 2005
Interview conducted after ASH 2005
Dr. Goh Yeow Tee, MBBS, M Med(Internal Med), Senior Consultant,
Department of Haematology, Head, Bone Marrow Transplant, Director,
Haematology Center, Singapore General Hospital, was kind enough to share his
thoughts on advances in CML treatment in an interview conducted by Anjana Rai
Chaudhuri, PhD, co-founder of the Asian CML Support Group. Dr. Goh was
Principal Investigator of the Phase II Gleevec trials in Singapore and is currently
the Principal Investigator of the Phase II/Phase III Dasatinib trials and Phase II
AMN107 trial. In addition, Dr. Goh heads the Bone Marrow Transplant Unit at
SGH.
Department of Haematology, Head, Bone Marrow Transplant, Director,
Haematology Center, Singapore General Hospital, was kind enough to share his
thoughts on advances in CML treatment in an interview conducted by Anjana Rai
Chaudhuri, PhD, co-founder of the Asian CML Support Group. Dr. Goh was
Principal Investigator of the Phase II Gleevec trials in Singapore and is currently
the Principal Investigator of the Phase II/Phase III Dasatinib trials and Phase II
AMN107 trial. In addition, Dr. Goh heads the Bone Marrow Transplant Unit at
SGH.
Anjana: Dr. Goh, thank you for sharing your thoughts on CML treatment and
management for the benefit of CML patients and caregivers. The 47th Annual Meeting of
the American Society of Hematology has just concluded in Atlanta, Georgia. I understand
that you attended the meeting. Where does CML treatment stand compared to other
hematologic malignancies?
Dr. Goh: CML has become the posterchild for molecularly targeted disease with Imatinib
showing good solid long-term remissions. Due to the fact that BCR-ABL is the primary
target in CML, drugs that are molecular inhibitors have been designed to control the disease.
Other malignancies like MDS has seen advances with the drug Revlimid and Multiple
Myeloma has also seen advances but the most rapid advances in understanding and
controlling the disease has been in chronic myeloid
leukemia.
Anjana: We are hearing that transplants are being done less and less in CML. Is that true?
Dr. Goh: Yes, it is. We were doing at least 20 CML transplants a year in ourclinic before,
but now the rate has fallen to less than 5 a year for CML.
Anjana: You are a transplant specialist and you ran the Gleevec drug trials and now running
the Dasatinib and AMN107 trials. That places you in a unique position to comment on the
role of allogeneic transplant in the Imatinib era.
Dr. Goh: For CML, I would say the role of transplant now is mainly that of
salvage therapy in case drug treatment fails. Newly diagnosed patients who are
35 years old and below and have sibling donors are given the choice of upfront
transplant in our clinic.
Anjana: Is the recommendation for transplant also based on the phase of disease?
Dr. Goh: For patients diagnosed in accelerated or blast phase, we bring them back to
chronic phase by drug treatment and if transplant risks are favorable, recommend
transplant. Our success rate of CML transplant in the advanced phases is about 30%
long-term survivals. For patients who relapse on Gleevec, we now have the Dasatinib and
AMN107 trials to offer to them and again, those who are young and have sibling donors
are given the choice of allogeneic transplant.
Anjana: Mini-transplants are done in your clinic. Tell us your thoughts on mini-transplants.
Dr. Goh: We recommend minitransplants to patients who are older. I would say that the
survival rates with mini-transplants are same as that with classical transplants.
Anjana: What about cord blood transplants?
Dr. Goh: Yes, we do umbilical cord blood transplants. Singapore now has a public cord
blood bank so this is a step forward. The problem with cord blood transplants on CML
patients is that we see a higher rate of graft rejection and the graft cell dose is very
important.
Anjana: I understand that double cord blood transplants are done here, taking cells from
two cord blood units for adult transplants. What about trying to do exvivo expansion of
cord blood cells so that the cell dose is adequate?
Dr. Goh: We have done a few double cord blood transplants and that is one way of
overcoming the lack of adequate cell dose from a single cord blood unit. Currently, we are
in the process of validating ex-vivo cord blood expansion in our laboratories here. With the
advent of our own public cord blood bank, we will be able to help patients who need
transplants but do not have adult matched donors.
Anjana: The 54-month data from the IRIS trials has been updated and the progression rate
seems to be falling with time? What is the long-term prognosis for Gleevec patients in
chronic phase?
Dr. Goh: The prognosis is very good. The updated trial results showed 92% of
newly diagnosed patients on 400mg Gleevec achieve major remission and
86% complete remission with an overall survival of 90%. This bodes well for
Gleevec therapy in new patients.
Anjana: Based on the IRIS trials, there is the 3-log reduction in PCR values
milestone to reach in one year of Gleevec therapy. If your Gleevec patients do not
reach this milestone, do you increase the Gleevec dose or add other agents? Also,
the 800mg Gleevec trial results from MDACC shows faster rate of remission
and higher rate of PCRUs, what are your thoughts on starting newly diagnosed
patients on 800mg Gleevec?
Dr. Goh: Talks were presented at ASH 2005 that showed that PCR values go on
decreasing with time even up to 4 years. Therefore, even if my Gleevec patients do
not reach 3-log reduction in a year of therapy, I will monitor their PCR values without
increasing their dose and as long as the PCR values are stable or decreasing, I would not
change dose. In our experience with the Gleevec trials and treating Asian patients, we have
found that Asian patients do not tolerate 800mg dose Gleevec very well. If a newly
diagnosed patient is high-risk by Sokal score and is young, I may start the patient on 600mg
Gleevec. The 600mg dose has been seen to give good results with tolerable toxicity in the
Australian TIDEL trial run by Dr. Timothy Hughes.
Anjana: You are currently running the Phase II and Phase III Dasatinib trials. You also ran
the Gleevec Phase II trials. What is your general impression of
Dasatinib?
Dr. Goh: Good. We are seeing promising results in Gleevec-resistant patients, those with
ABL point mutations and those without. The data from ASH 2005 for Phase II Chronic
Phase CA180013 studies showed a 31% major remission rate and a 25% complete
remission rate at the 3-month mark. 90% of patients from the Phase I Dasatinib trial in
chronic phase remain in response with the rate of 40% major remission and 33% complete
response. These are patients who may have had disease for some time and were resistant
to Gleevec so this is a good result from this new drug.
Anjana: What are your thoughts on Dasatinib side-effects?
Dr. Goh: We see myelosuppression (low counts) as a major side-effect as also seen
worldwide and reported at ASH. This rate is about 38% in the chronic phase Phase I trial
and more in advanced phases.
Anjana: How do you find the management of side-effects in the Dasatinib trials compared
to Gleevec trials?
Dr. Goh: There is severe myelosuppression in advanced phase patients in the Dasatinib
trial, especially for patients who have had the disease more than 8 years. This degree of
myelosuppression seen is more in the Dasatinib trial compared to what I saw in the Gleevec
trials. However, patients have said that other side-effects are less on Dasatinib compared to
Gleevec. It is easier to manage chronic phase Dasatinib patients compared to the
advanced phases.
Anjana: Has pleural effusion been a problem in the Singapore Dasatinib trials?
Dr. Goh: About 10% as seen in worldwide trials. Pleural effusion requires intervention and
close monitoring but it is not unmanageable.
Anjana: Patients on Dasatinib are concerned about their low counts on the
drug. How do you manage such patients? Gleevec in the Phase II trials was stopped when
platelet count reached 50,000. Do you stop Dasatinib if the patient reaches 50,000 platelet
count?
Dr. Goh: We do manage patients aggressively, especially in the advanced phase trials
without many drug interruptions and try to support by platelet transfusions. Low absolute
neutrophil count seen in the Dasatinib trial is not as common as low platelet
count. We do not generally stop the drug until ANC reaches 500 and will use
growth factor support, if needed. The patients in the trial have had the disease
for long hence the aggressive management of disease.
Anjana: Nowadays, with both Gleevec and Dasatinib, doctors are much more willing to
treat with growth factors for low counts rather than stop the drug. Why is that?
Dr. Goh: With Gleevec patients, sometimes, we have seen that drug
breaks due to low counts result in better tolerance when the drug is reintroduced. However,
in the case of some patients, treatment has to be aggressive and the patient needs to stay on
the drug with growth factor/transfusion support. So, we do both as needed.
Anjana: In most CML centers, PCR testing has become the norm to monitor minimal
residual disease. However, patients agonize over bouncing PCR values. Do you think this
has to do with the perfection of technique or disease fluctuation or both?
Dr. Goh: Both. However, technique does need to be perfected to give more stable values
over time and a worldwide standardization is welcome. 3 top CML centers in the world are
currently working on such PCR standardization. In the meantime, I would advise patients
not to be worried by minor bounces.
Anjana: What kind of a PCR bounce is deemed worrisome?
Dr. Goh: With my patients, if there is a 1-log increase in PCR values, I recommend
re-testing as well as bone marrow cytogenetics and morphology
testing.
Anjana: Do you think that there is no place for FISH anymore in CML monitoring?
Dr. Goh: On the contrary, FISH testing has a place in CML monitoring when a patient is
not yet in CCR. It is a good technique to use then and frequent testing can be done as
FISH can be done from
peripheral blood.
Anjana: Some doctors are not recommending BMA cytogenetics anymore for routine CML
monitoring. What is your recommendation to your patients? And why?
Dr. Goh: I recommend yearly BMA cytogenetics for patients in CCR and half-yearly for
patients not in CCR. FISH and PCR testing cannot give information on chromosomal
changes in the marrow and a BMA cytogenetics is still the only way of monitoring for
additional chromosomal abnormalities, especially in Ph negative cells.
Anjana: Have you seen Ph negative clonal evolution in your patients?
Dr. Goh: Yes, I have one patient having trisomy 8, she is continuing doing well
on Gleevec. Several talks on this were presented at ASH. The presentation of
the IRIS trial data as well as the study from MD Anderson Cancer Center on
first-line Gleevec patients showed a 5-7% incidence of Ph negative clones with Gleevec
and in many instances this phenomenon was transient and there were only rare cases of
MDS and acute leukemia. However, close monitoring of CML in patients developing Ph
negative chromosomal abnormalities is advised with examination of bone marrow,
periodically, for the presence of dysplastic features.
Anjana: Dr. Charles Chuah is doing ABL point mutations testing in our
clinic. Do you think that mutations testing is going to be used very commonly and even at
diagnosis?
Dr. Goh: I think mutations testing will become common and used to evaluate the
mechanism of resistance in patients having a sub-optimal response to Gleevec. Since new
kinase inhibitors are now available as well as the transplant option, these tests will enable us
to choose an alternative therapy early on if the patient is not having an optimal response to
Gleevec.
Anjana: Is it possible to predict from diagnosis whether Gleevec will work well for the
patient or not? Now that there are alternative drugs and therapies, it would be good for
patients to know early on whether they are good candidates for Gleevec.
Dr. Goh: At ASH 2005, there were talks presented on gene expression profiling and
research still goes on in this arena and hopefully will help isolate newly diagnosed patients
in need of more aggressive therapy than Gleevec. There were other testing methods
presented at ASH having a bearing on drug concentrations of Gleevec in CML cells, drug
efflux and plasma levels of Gleevec. My advice to patients is to wait and see which tests
actually become the norm as some of the testing is quite time consuming and expensive.
Anjana: Were there any talks presented at ASH on CML quiescent cells and persistence of
disease with Gleevec?
Dr. Goh: Yes, several. One of them was the drug from Bristol-Myers-Squibb, a
farnesyl transferase inhibitor that in combination with kinase inhibitors, has
activity against CML quiescent cells in the lab. Again, research on molecular
persistence of disease and its reasons is ongoing and time will bring forth
breakthroughs in this area.
Anjana: Dr. Goh, I would like to thank you on behalf of the Asian CML Support
Group patients and caregivers for sharing your thoughts on CML treatments. One
last question. Do you think there will be a drug cure one day in CML?
Dr. Goh: Yes, I am optimistic about that since the disease is being controlled in
more and more patients and a lot of research is still going on targeting the
mechanisms of disease persistence and resistance to therapies. It is generally
believed that stimulation of host immune systems by Interferon, GMCSF and
immunotherapies like vaccines will play a role in the future of CML drug cure.
management for the benefit of CML patients and caregivers. The 47th Annual Meeting of
the American Society of Hematology has just concluded in Atlanta, Georgia. I understand
that you attended the meeting. Where does CML treatment stand compared to other
hematologic malignancies?
Dr. Goh: CML has become the posterchild for molecularly targeted disease with Imatinib
showing good solid long-term remissions. Due to the fact that BCR-ABL is the primary
target in CML, drugs that are molecular inhibitors have been designed to control the disease.
Other malignancies like MDS has seen advances with the drug Revlimid and Multiple
Myeloma has also seen advances but the most rapid advances in understanding and
controlling the disease has been in chronic myeloid
leukemia.
Anjana: We are hearing that transplants are being done less and less in CML. Is that true?
Dr. Goh: Yes, it is. We were doing at least 20 CML transplants a year in ourclinic before,
but now the rate has fallen to less than 5 a year for CML.
Anjana: You are a transplant specialist and you ran the Gleevec drug trials and now running
the Dasatinib and AMN107 trials. That places you in a unique position to comment on the
role of allogeneic transplant in the Imatinib era.
Dr. Goh: For CML, I would say the role of transplant now is mainly that of
salvage therapy in case drug treatment fails. Newly diagnosed patients who are
35 years old and below and have sibling donors are given the choice of upfront
transplant in our clinic.
Anjana: Is the recommendation for transplant also based on the phase of disease?
Dr. Goh: For patients diagnosed in accelerated or blast phase, we bring them back to
chronic phase by drug treatment and if transplant risks are favorable, recommend
transplant. Our success rate of CML transplant in the advanced phases is about 30%
long-term survivals. For patients who relapse on Gleevec, we now have the Dasatinib and
AMN107 trials to offer to them and again, those who are young and have sibling donors
are given the choice of allogeneic transplant.
Anjana: Mini-transplants are done in your clinic. Tell us your thoughts on mini-transplants.
Dr. Goh: We recommend minitransplants to patients who are older. I would say that the
survival rates with mini-transplants are same as that with classical transplants.
Anjana: What about cord blood transplants?
Dr. Goh: Yes, we do umbilical cord blood transplants. Singapore now has a public cord
blood bank so this is a step forward. The problem with cord blood transplants on CML
patients is that we see a higher rate of graft rejection and the graft cell dose is very
important.
Anjana: I understand that double cord blood transplants are done here, taking cells from
two cord blood units for adult transplants. What about trying to do exvivo expansion of
cord blood cells so that the cell dose is adequate?
Dr. Goh: We have done a few double cord blood transplants and that is one way of
overcoming the lack of adequate cell dose from a single cord blood unit. Currently, we are
in the process of validating ex-vivo cord blood expansion in our laboratories here. With the
advent of our own public cord blood bank, we will be able to help patients who need
transplants but do not have adult matched donors.
Anjana: The 54-month data from the IRIS trials has been updated and the progression rate
seems to be falling with time? What is the long-term prognosis for Gleevec patients in
chronic phase?
Dr. Goh: The prognosis is very good. The updated trial results showed 92% of
newly diagnosed patients on 400mg Gleevec achieve major remission and
86% complete remission with an overall survival of 90%. This bodes well for
Gleevec therapy in new patients.
Anjana: Based on the IRIS trials, there is the 3-log reduction in PCR values
milestone to reach in one year of Gleevec therapy. If your Gleevec patients do not
reach this milestone, do you increase the Gleevec dose or add other agents? Also,
the 800mg Gleevec trial results from MDACC shows faster rate of remission
and higher rate of PCRUs, what are your thoughts on starting newly diagnosed
patients on 800mg Gleevec?
Dr. Goh: Talks were presented at ASH 2005 that showed that PCR values go on
decreasing with time even up to 4 years. Therefore, even if my Gleevec patients do
not reach 3-log reduction in a year of therapy, I will monitor their PCR values without
increasing their dose and as long as the PCR values are stable or decreasing, I would not
change dose. In our experience with the Gleevec trials and treating Asian patients, we have
found that Asian patients do not tolerate 800mg dose Gleevec very well. If a newly
diagnosed patient is high-risk by Sokal score and is young, I may start the patient on 600mg
Gleevec. The 600mg dose has been seen to give good results with tolerable toxicity in the
Australian TIDEL trial run by Dr. Timothy Hughes.
Anjana: You are currently running the Phase II and Phase III Dasatinib trials. You also ran
the Gleevec Phase II trials. What is your general impression of
Dasatinib?
Dr. Goh: Good. We are seeing promising results in Gleevec-resistant patients, those with
ABL point mutations and those without. The data from ASH 2005 for Phase II Chronic
Phase CA180013 studies showed a 31% major remission rate and a 25% complete
remission rate at the 3-month mark. 90% of patients from the Phase I Dasatinib trial in
chronic phase remain in response with the rate of 40% major remission and 33% complete
response. These are patients who may have had disease for some time and were resistant
to Gleevec so this is a good result from this new drug.
Anjana: What are your thoughts on Dasatinib side-effects?
Dr. Goh: We see myelosuppression (low counts) as a major side-effect as also seen
worldwide and reported at ASH. This rate is about 38% in the chronic phase Phase I trial
and more in advanced phases.
Anjana: How do you find the management of side-effects in the Dasatinib trials compared
to Gleevec trials?
Dr. Goh: There is severe myelosuppression in advanced phase patients in the Dasatinib
trial, especially for patients who have had the disease more than 8 years. This degree of
myelosuppression seen is more in the Dasatinib trial compared to what I saw in the Gleevec
trials. However, patients have said that other side-effects are less on Dasatinib compared to
Gleevec. It is easier to manage chronic phase Dasatinib patients compared to the
advanced phases.
Anjana: Has pleural effusion been a problem in the Singapore Dasatinib trials?
Dr. Goh: About 10% as seen in worldwide trials. Pleural effusion requires intervention and
close monitoring but it is not unmanageable.
Anjana: Patients on Dasatinib are concerned about their low counts on the
drug. How do you manage such patients? Gleevec in the Phase II trials was stopped when
platelet count reached 50,000. Do you stop Dasatinib if the patient reaches 50,000 platelet
count?
Dr. Goh: We do manage patients aggressively, especially in the advanced phase trials
without many drug interruptions and try to support by platelet transfusions. Low absolute
neutrophil count seen in the Dasatinib trial is not as common as low platelet
count. We do not generally stop the drug until ANC reaches 500 and will use
growth factor support, if needed. The patients in the trial have had the disease
for long hence the aggressive management of disease.
Anjana: Nowadays, with both Gleevec and Dasatinib, doctors are much more willing to
treat with growth factors for low counts rather than stop the drug. Why is that?
Dr. Goh: With Gleevec patients, sometimes, we have seen that drug
breaks due to low counts result in better tolerance when the drug is reintroduced. However,
in the case of some patients, treatment has to be aggressive and the patient needs to stay on
the drug with growth factor/transfusion support. So, we do both as needed.
Anjana: In most CML centers, PCR testing has become the norm to monitor minimal
residual disease. However, patients agonize over bouncing PCR values. Do you think this
has to do with the perfection of technique or disease fluctuation or both?
Dr. Goh: Both. However, technique does need to be perfected to give more stable values
over time and a worldwide standardization is welcome. 3 top CML centers in the world are
currently working on such PCR standardization. In the meantime, I would advise patients
not to be worried by minor bounces.
Anjana: What kind of a PCR bounce is deemed worrisome?
Dr. Goh: With my patients, if there is a 1-log increase in PCR values, I recommend
re-testing as well as bone marrow cytogenetics and morphology
testing.
Anjana: Do you think that there is no place for FISH anymore in CML monitoring?
Dr. Goh: On the contrary, FISH testing has a place in CML monitoring when a patient is
not yet in CCR. It is a good technique to use then and frequent testing can be done as
FISH can be done from
peripheral blood.
Anjana: Some doctors are not recommending BMA cytogenetics anymore for routine CML
monitoring. What is your recommendation to your patients? And why?
Dr. Goh: I recommend yearly BMA cytogenetics for patients in CCR and half-yearly for
patients not in CCR. FISH and PCR testing cannot give information on chromosomal
changes in the marrow and a BMA cytogenetics is still the only way of monitoring for
additional chromosomal abnormalities, especially in Ph negative cells.
Anjana: Have you seen Ph negative clonal evolution in your patients?
Dr. Goh: Yes, I have one patient having trisomy 8, she is continuing doing well
on Gleevec. Several talks on this were presented at ASH. The presentation of
the IRIS trial data as well as the study from MD Anderson Cancer Center on
first-line Gleevec patients showed a 5-7% incidence of Ph negative clones with Gleevec
and in many instances this phenomenon was transient and there were only rare cases of
MDS and acute leukemia. However, close monitoring of CML in patients developing Ph
negative chromosomal abnormalities is advised with examination of bone marrow,
periodically, for the presence of dysplastic features.
Anjana: Dr. Charles Chuah is doing ABL point mutations testing in our
clinic. Do you think that mutations testing is going to be used very commonly and even at
diagnosis?
Dr. Goh: I think mutations testing will become common and used to evaluate the
mechanism of resistance in patients having a sub-optimal response to Gleevec. Since new
kinase inhibitors are now available as well as the transplant option, these tests will enable us
to choose an alternative therapy early on if the patient is not having an optimal response to
Gleevec.
Anjana: Is it possible to predict from diagnosis whether Gleevec will work well for the
patient or not? Now that there are alternative drugs and therapies, it would be good for
patients to know early on whether they are good candidates for Gleevec.
Dr. Goh: At ASH 2005, there were talks presented on gene expression profiling and
research still goes on in this arena and hopefully will help isolate newly diagnosed patients
in need of more aggressive therapy than Gleevec. There were other testing methods
presented at ASH having a bearing on drug concentrations of Gleevec in CML cells, drug
efflux and plasma levels of Gleevec. My advice to patients is to wait and see which tests
actually become the norm as some of the testing is quite time consuming and expensive.
Anjana: Were there any talks presented at ASH on CML quiescent cells and persistence of
disease with Gleevec?
Dr. Goh: Yes, several. One of them was the drug from Bristol-Myers-Squibb, a
farnesyl transferase inhibitor that in combination with kinase inhibitors, has
activity against CML quiescent cells in the lab. Again, research on molecular
persistence of disease and its reasons is ongoing and time will bring forth
breakthroughs in this area.
Anjana: Dr. Goh, I would like to thank you on behalf of the Asian CML Support
Group patients and caregivers for sharing your thoughts on CML treatments. One
last question. Do you think there will be a drug cure one day in CML?
Dr. Goh: Yes, I am optimistic about that since the disease is being controlled in
more and more patients and a lot of research is still going on targeting the
mechanisms of disease persistence and resistance to therapies. It is generally
believed that stimulation of host immune systems by Interferon, GMCSF and
immunotherapies like vaccines will play a role in the future of CML drug cure.
Dr. Goh Yeow
Tee, Singapore
General Hospital,
Singapore
Tee, Singapore
General Hospital,
Singapore