CMLNews: Dr. Nicolini, warm thanks for taking the time to talk to worldwide CML patients
and caregivers on the disease, current treatments and the future of CML in our on-line CML
Support Group, AsianCMLSupport. The 5-year results from the IRIS trials give us a lot of hope
for the future, with the relapse rate decreasing with time. Does this mean that patients in
remission can hope to stay on the drug for many years?
Dr. Nicolini: Yes certainly. After 60 months of follow-up, the rate of disease progression is 0%,
this is VERY encouraging for all the patients who have achieved an optimal response. If this
trend is confirmed in the coming years Glivec will continue to be used as a first line treatment.
CMLNews: Although Gleevec has worked so well for chronic phase patients, it is not a drug
cure. What are your opinions on treatments targeted to eradicate minimal residual disease,
specifically, Interferon?
Dr. Nicolini: First of all, we are not yet sure that Glivec/Gleevec alone does not cure the disease
in certain cases. We performed a pilot study in France on a small cohort of patients who had
reached complete molecular remission (RQ-PCR negative) for 2 consecutive years on at least 8
separate samples. We stopped Glivec/Gleevec in these patients and RQ PCR was performed
monthly so as to detect an eventual molecular relapse as soon as possible and in order that
Glivec/Gleevec be restarted immediately. Half of the patients relapsed and restarted their
Glivec/Gleevec, these patients regained complete molecular remission. The remaining half of the
patients did not relapse, this indicates that some of them might be definitively cured. The first
patient in this study has now been off Glivec/Gleevec for 36 months. Interestingly, all of the
patients who did not relapse after the withdrawal of Glivec/Gleevec, had previously taken
Interferon, while all of those who relapsed had not necessarily taken Interferon in the past, prior
to Glivec/Gleevec.
Secondly, in the patients with remaining residual disease, the addition to Glivec/Gleevec of
another compound with a different action on leukemic cells might be interesting. For example,
Interferon or BCR-ABL vaccines might be interesting tools to use, and some trials are currently
being drawn up or are already underway in different centers.
CMLNews: We hear that centers are starting to do Gleevec concentration in the blood testing.
Can you please explain its significance and is there a therapeutic concentration that patients
should have on 400mg dose?
Dr. Nicolini: This is true. This work was pioneered at Bordeaux, in France. They determined
Glivec/Gleevec concentrations in plasma in cohorts of patients that had responded well to
Glivec/Gleevec (ie patients in major molecular response: MMR) aswell as in patients with
suboptimal response (ie no MMR). Patients in MMR were found to have significantly higher
plasmatic concentrations in their blood. A vast study is currently underway to determine whether
this is confirmed on larger cohorts of patients. We now envisage designing trials in which
Glivec/Gleevec doses would be adjusted to their plasmatic concentrations. In addition the
determination of plasma concentration may also be of help in case of drug-drug interactions
(there are many) or gut disease.
It is very important to measure the trough plasmatic concentrations (when the drug is taken once
a day) ie, just before the next pill is taken, so residual concentrations are extremely important.
Under these circumstances the optimal trough concentration determined by the Bordeaux team is
1000 ng/ml.
CMLNews: Dr. Nicolini, you have had experience treating patients with Dasatinib and Nilotinib.
Can you tell us which drug, in your experience, is better in terms of response and side-effects for
Gleevec-resistant patients? Is pleural effusion on Dasatinib widespread?
Dr. Nicolini: This is a difficult question. My feeling is that for advanced phase patients
(accelerated and blastic) Dasatinib seems -to me- more efficient than Nilotinib, despite sometimes
severe side effects. For chronic phases both drugs seem equivalent and Nilotinib is relatively well
tolerated (sometimes even better than Glivec/Gleevec). However these drugs have never been
compared in a randomized trial, so I cannot answer more precisely. According to the mutation
status, patients will not respond as well to Nilotinib or Dasatinib, but this may vary according to
the type of mutation.
Pleural effusions are of concern in patients on Dasatinib because they are relaively frequent
(about 20% of the patients (all grades) in trials with 140 mg/day, all phases combined) these are
sometimes severe and necessitate thoracocentesis. However, recent studies show that if the drug
is taken once a day rather than twice a day and at somewhat lower doses of 100 mg/day, this will
lead to equivalent efficacy with less adverse events (and pleural effusions).
CMLNews: There are patients who are resistant to Dasatinib and Nilotinib with the T315I
mutation. Not many centers are running aurora kinase inhibitor trials around the world. Are
there any therapies these patients can do if they are not eligible for allogeneic transplant?
Dr. Nicolini: Yes there are. A recent case report in Blood journal indicates that a chronic phase
patient with a T315I mutation might benefit from Interferon; although fairly slowly, but surely. In
addition, just last week, I presented data to the European School of Haematology meeting
concerning the fact that we are seeing very interesting results in chronic phase patients with
subcutaneous Homo-Harringtonine (HHT), a chemotherapeutic compound -but very well
tolerated (no hair loss, few nausea)- administrable at home for a 14-day course on the first
instance and then 7-days maintenance courses. All the patients treated in our center have seen
their T315I mutated transcripts drop to 0% after 3 courses, which is very encouraging. However,
the method of detection of T315I transcripts is not very sensitive. The response on wild type
cells (ie non mutated) is much slower though. Some oral inhibitors for T315I mutation will come
soon into trials as well.
CMLNews: There are a few patients who remain 100%Ph+ with Gleevec and Sprycel but have
no BCR-ABL mutations. Is allogeneic transplant the only option for them?
Dr. Nicolini: Patients who remain 100% Ph+ without any mutation on Gleevec/Glivec might
obtain a response with the second-generation tyrosine kinase inhibitors, particularly Sprycel, as
this compound acts not only on the Philadelphia chromosome, but also on other pathways (SRC
kinases) that can be involved in the leukemic process. However, there are some patients on
Sprycel who do not show any cytogenetic response, and do not harbour mutations. We suspect
that there are other untargeted pathways that can explain the resistance of leukemic cells to this
compound. In these patients, the adjunction of low doses of Interferon to Sprycel might help.
The presence of an HLA histocompatible (sibling or not) donor, the patient age, the disease
phase, the patient’s geographical location have to be considered, and indeed, we believe that
allogeneic stem cell transplantation might be an interesting option.
CMLNews: Patients on sequential kinase inhibition inhibitors have developed some incidences of
mutations. In your opinion, are combination therapies of kinase inhibitors a better approach to
treating CML today?
Dr. Nicolini: It is difficult to speculate on that this 2007. If we consider that Glivec/Gleevec
resistance through mutations mimicks what happened with HIV infections (the virus behaved like
a leukemic cell, developing additional mutatons in order to survive) treated with combined anti-
retroviral therapies, the answer might be yes. But mutations are not the only means of leukemic
cells escaping from Glivec/Gleevec-induced death. In my opinion, in advanced phases (where
mutations are a frequent cause of Glivec/Gleevec resistance), such therapies might be very
interesting, but for the very early phases of chronic phase CML, I believe that a single high-
affinity specific compound (ie Nilotinib) would be more interesting to use, because at the onset of
CML, the Ph oncogene alone is responsible for driving the disease, not other pathways, and BCR-
ABL mutations are quite exceptional at this stage.
CMLNews: We understand the basis for the design of the combo trial MK-0457+Dasatinib
since Dasatinib alone cannot overcome the T315I mutation. Will side-effects be a major problem
in such combo therapies?
Dr. Nicolini: I suspect yes. We have these two compounds in our department but their
hematological tolerance, when taken alone, does not seem to be very good (even in chronic phase
patents) this is why their combination might be problematic.
CMLNews: Is there any basis for designing a trial with Gleevec + Dasatinib in combination?
Dr. Nicolini: Dr Shah has reported that this might be an important option. He showed that some
patients who were resistant to Glivec/Gleevec, and then went on to take Dasatinib, developed
Dasatinib resistance. These patients then resumed Glivec/Gleevec therapy with interesting
secondary responses. In addition, Glivec/Gleevec inhibits c-kit which, at high levels, is a surface
receptor for a stem cell factor, the activation of this pathway might participate in disease
progression. Dasatinib is much less active on c-kit and does not inhibit consistently this pathway.
Therefore these arguments could provide good reasons for conducting Dasatinib +
Glivec/Gleevec trials.
CMLNews: For patients in CCR not reaching major molecular response on any dose of
Gleevec, would switching to Dasatinib or Nilotinib help? Recent data shows that newly
diagnosed patients treated with Dasatinib reached CCR fast but did not reach the same
percentage of MMRs as high dose Gleevec at the end of one year of therapy. Would it be more
advisable for patients not in MMR on Gleevec to try vaccine trials? Do you think vaccines are
going to work in the future to eradicate minimal residual disease?
Dr. Nicolini: Firstly, switching to Dasatinib or Nilotinib in such patients is currently being tested
in randomized international trials, so we cannot yet answer this question. For the few patients we
have enrolled in our department in this trial with a short follow-up (9 months maximum)
consistent improvements in the molecular response remain to be seen.
Secondly, and again, Dasatinib and high dose Glivec/Gleevec have not yet been compared in a
randomized trial, so we cannot ascertain that your statement is true. In addition Nilotinib might be
a more interesting compound in this regard, because of its high affinity and specificity for BCR-
ABL (the Philadelphia chromosome) with less adverse events, but this compound has not been
compared to high dose Glivec/Gleevec in a randomized manner as well. Some academics, as well
as industrial randomized trials (Glivec/Gleevec versus Dasatinib, Glivec/Gleevec versus Nilotinib)
are currently underway in a number of countries, and will be able to provide a suitable answer to
your question.
Regarding vaccine trials, I think that these kind of strategies will be the most efficient in the case
of low disease burden (ie in patients in MMR), because the immunological response might not be
strong enough to eradicate the disease in patients with a higher disease burden (these are the
lessons previously learnt from the reponses to donor lymphocyte infusions for
molecular/cytogenetic/ hematologic relapse after allogeneic stem cell transplantation).
Yes, I do believe that some vaccines will work in some CML patients with minimal residual
disease in the future and that these patients might well be cured. Dr Bocchia showed and
published some interesting data in this regard, but these strategies require further improvement.
CMLNews: One more question. We have heard that trials are going on in France and Australia
of patients in PCRU going off Gleevec to see if they remain in remission. Can you comment on
these trials?
Dr. Nicolini: This is a very interesting story, however it currently concerns only limited numbers
of patients, and, unfortunately. I can only comment on the French trial. I already described the
results we obtained in France in the pilot study in your question #2. This study has now been
extended to higher numbers of CML patients with the same inclusion criteria, as mentioned
above, in a multicentric French trial. We aim to determine whether the results obtained in the
pilot study were just due to luck or whether what we found in limited numbers of patients is a
general concern. We are now thinking of adding low doses of Interferon for patients with
molecular relapse, in order to enhance an eventual immunological response to Ph+ leukemic cells
and try to reconvert these patients to a complete molecular remission state.
CMLNews: Thank you for your time, Dr. Nicolini. We are grateful to hear the views of a
French CML expert.
Dr. Nicolini: Thanks for your invitation. That was a great pleasure to answer to your pertinent
questions. I hope that my answers will be helpful to CML patients worldwide.
| Dr. Franck-Emmanuel Nicolini, Hematologist from The Hematology Department, University Hospital Edouard Herriot, Lyon, France and a French CML Expert was interviewed by Barbara Meunier and Anjana Rai Chaudhuri of CMLNews, the Asian CML Support Group Newsletter. Interview Date: September, 2007 |