Download Chronic Myeloid Leukemia: The Poster Child of

Chronic Myeloid Leukemia: The Poster Child of Targeted Therapy Achieves
Adolescence
This was a three-part presentation Education Session and the presenters were
Dr. Cortes, MD Anderson, Dr. Saglio, University of Turin, and Dr. M Deininger,
OHSU.
Dr. Cortes: Imatinib and Beyond – Exploiting the Full Potential of Targeted
Therapy for CML
Dr. Cortes gave an overview of the history leading up to the development of
Imatinib (Gleevec), as well as the current information from the IRIS data. The
emphasis is on the patients in whom IM therapy fails, or who initially respond
and later relapse and in trying to understand and determine which patients will
respond to the drug either at standard treating doses (400mg daily) or
escalated dose. Discussions are on going in the area of plasma level monitoring
because there is no prospective measure of levels undertaken to account for
intrapatient variability and changes that occur with dose adjustments and
other factors. There needs to be more investigation in to whether dose plasma
level testing can be used to help navigate therapy and minimize adverse
events. Interestingly, Dr. Cortes mentioned that only a loss of major
cytogenetic response is scored as an event, but that the goal of therapy at the
very least is to achieve a complete cytogenetic response, as it is associated
with the most significant survival benefit. Achieving CCR at 12 mos. indicates
an excellent transformation free survival. He pointed out that patients with
suboptimal response to Imatinib are being recognized at an increasing rate.
The need to closely monitor for the first 6 months of therapy is quite critical to
improve outcomes for patients.
He spoke about 2nd generation TKI’s:
Dasatinib (Sprycel) – Considered to be one of the most potent inhibitor of BCR
ABL and also a potent inhibitor of the SFK (Src Family of Kinase) as well as
PDGFR (Platelet Derived Growth Inhibitor) and c-Kit. He reiterated the Phase II
clinical trial data – 53% percent of patients in CP phase being treated with
Dasatinib after IM failure achieved CCR, 33% in AP, 27% in BP and 46% in LB
(lymphoid Blast). Duration of these responses correlates with the stage of the
disease with PFS (Progression free survival) of 80% for CP, 46% in AP.
Consequently, PFS for BP and LP base is 5.6 and 3.1 months respectively. The
most significant adverse events were myelosuppression (grade 3.4 neutropenia
and thrombocytopenia in nearly 50%) Pleural effusion, GI hemorrhage
(particularly in advanced stages). He reminded us that alternative study
comparing 100mg once daily versus 70 mg BID showed decrease in s/e of PE or
MS with the response to therapy being identical.
Nilotinib (Tasigna) – A modified IM structure to improve binding affinity. It is
30 fold more potent inhibitor of BCR ABL while maintaining similar activity as
IM against PDGFR and C-Kit. Rates of CCyR for patients treated in the CP phase
were 41% and rates for those treated in AP were 19%. Responses have been
durable with sustained Major cytogenetic responses at 18 mos. in 84% of
patients in the CP phase. In AP the PFS was 57% at 12 mos. The most
significant toxicities were: myelosuppression and biochemical abnormalities
(elevation of bilirubin, lipase and glucose) that have been typically transient
and asymptomatic. There is also the potential for QTc prolongation, although
less than 3% of patients have had significant prolongation (most frequently
asymptomatic).
Bosutinib – Inhibitor of BCR ABL and SFK with little if any effect on PDGFR and
c-KIT. Phase II studies showed that Major cytogenetic response of 41% (CCR in
30%) of the patients in CP who failed IM despite median follow up of only 3
months. A potential advantage of a narrower kinase inhibitor is the potential
to decrease toxicity attributed to off-targeted effects. No drug related pleural
effusions and myelosuppression has been minimal 3/4 thrombocytopenia.
INNO-406 – Potent BCR ABL inhibitor, also inhibits Lyn a member of SFK but not
other members of SFK. It is currently under Phase I. Most patients in this trial
have either failed IM and other TKI’s and in spite of this, responses have been
observed in 7 of the 24 patients.
The important clinical question is how to choose a 2nd TKI for patients in whom
IM has failed. It is hard to compare the results of all the clinical trials for these
agents for various reasons. Looking at side effect profiles for the various drugs
can help the clinician to make decisions on behalf of the patient. For example
pleural effusions can occur up to 35% of patients on Dasatinib, depending on
the stage, dose, and schedule with risk factors including hypertension and prior
cardiac disease (on a personal note, as a patient on only 50mg once a day and
in PCRU, pleural effusions or any other side effect has never been an issue, I
wish BMS would look into the dosing flexibility potential of this drug). Nilotinib
has grade 3 and 4 elevation of bilirubin, lipase and glucose in up to 15% of
patients. With the warning of QTc prolongation, although the potential exists
for all of these TKI’s to cause QTc prolongation. With regards to mutations,
there is currently nothing available for T315I (note from CAS- there are a
couple of drugs in trial such as HHT from ChemGenex). Dasatinib has less
activity in vitro against F317L and both Dasatinib and Bosutinib have less
activity against V299L. Nilotinib has the least activity against some of the Ploop mutations, such as Y253H and E255 K/V. New mutations have developed
after therapy with a 2nd TKI. Nearly 50% of patients do not have detectable
mutations after failure with IM (discussed in more detail by later presentations
in this session).
It is reasonable to consider that the newer TKI’s could potentially improve
outcomes when used as frontline therapy because they are considerably more
potent. The idea being that if responses appeared faster and deeper it could
improve the outcomes, all three of the newer agents, Dasatinib, Nilotinib and
Bosutinib are undergoing frontline studies.
So, The conclusion is that the initial therapy is standard dose Gleevec, but
every opportunity to dose optimize and maximize patients response should be
of primary concern. Patients failing Gleevec have the options of the
availability of increasing number of 2nd generation TKI’s. The goal is adequate
monitoring, effective treatment options and improving the long-term
progression free survival of patients.