Download The poster sessions are an important highlight of these conferences

CML Posters ASCO – June 2008
The poster sessions are an important highlight of these conferences and very often herald exciting
new work that will eventually become more mainstream oral abstracts and published studies. Poster
sessions along with questions asked at the oral sessions are the main reason it is so important to
physically attend these conferences. There is much to be gained from hearing the interaction of the
many experts gathered to discuss these important topics. We have been working very hard to make
these conferences more patient friendly related to the cost of attendance and lodging facilities. We
seriously hope conference organizers of ASCO and hopefully ASH will take patient participation
seriously and help us to continue to make this more accessible to a wider patient population.
Summaries of the posters dedicated to 2nd generation TKI’s at ASCO:
Nilotinib in Pts with Ph+ CML in Blast Crisis (BC) Who are Resistant or Intolerant to Iminatinib Authors:
Francis J. Giles, Richard A Larson, Hagop M Kantarjiam, Philipp le Coutre, Francesca Palandri, Ariful
Haque, Neil Gallagher, Oliver G. Ottmann
Rationale:
- NL is a highly selective and potent inhibitor of BCR ABL and has demonstrated impressive efficacy
in the treatment of CML CP and CML AP of CML resistant or intolerant to IM
- CML BC is a disease phase with a high unmet medical need for which there are unlimited approved
or effective therapeutic treatment
- These results are presented with at least 11 months of follow up
-
Objectives:
To evaluate the efficacy of NL in pts with IM resistant or IM intolerant CML BC
To characterize the safety and tolerability of NL in pts with IM resistant or IM intolerant CML BC
Methods:
Phase II, open label multicenter
Adult pts with histologically confirmed IM resistant or IM intolerant CML BC
 30% blasts in PB (peripheral blood) or bone marrow (BM)
Extramedullary disease except liver or spleen
IM resistance was defined as :
o Tx with IM  600mg/day with
 Disease progression ( 50% increase in WBC, blasts, basophiles, or platelet counts)
 No hematologic response in BM after 4 weeks
 Tx with <600mg/day with mutations in any of the following sites in addition to
above:
 L248, G250, Q252,Y253,E255, T315,F317, or H396
- IM intolerance was defined as grade ¾ AE or grade 2 events persisting for  1 month while on IM
- 400 mg BID NL administered orally
- abscenec of safety concerns, after cycle 1, the dose could be escalated to 600 mg BID for:
o failure to achieve a return to CP
o loss of an achieved hematologic or cytogenetic response
o progressive disease
-
Results:
- 136 pts, Tx ongoing in 10
- 126 pts discontinued:
73 – disease progression
11 drug related AE
8 non-drug related AE
2 abnormal laboratory value
6 deaths
26 other (includes withdrawal of consent, administrative error, and protocol violation)
- NL achieved planned dosing in virtually all pts
- 38% of pts had dose interruptions; however, the duration of dose interruptions was short
Conclusions:
- NL is effective in pts with IM resistant or IM intolerant CML BC
- Overall survival is approximately 42% at 12 months in this pt population
- NL has a favorable safety profile
- NL is effective in pts with IM resistant or IM intolerant CML in myeloid BC or Lymphoid BC
Personal note: this poster did not raise the following points but seem obvious to me. NL offers a
chance for these pts in this advanced disease state to achieve CML CP and go forward with HSCT in a
healthier state. It also buys times for pts to locate suitable donors for HSCT
Minimal Cross Intolerance between Nilotinib and Imatinib in Patients with Imatinib Intolerant CML CP
or AP
Authors: Elias Jabbour, Andreas Hochhaus, Philipp le Coutre, Gianantonio Rosti, Kapil N Bhalla,
Ariful Haque, Neil Gallagher, Francis J. Giles, Jorge Cortes, Hagop M Kantarjian
Rationale:
-
NL is rationally designed, potent and highly selective inhibitor of BCR ABL
NL binds to ABL with higher affinity and improved topological fit compared to NL
NL was developed for the tx of IM intolerant or IM resistant CML Ph+
NL has highly significant clinical efficacy in pts with CML CP in the pivotal Phase II registration
trial
NL has low rates of grade ¾ myelosuppression
Objectives:
- To evaluate the incidence of cross intolerance between NL and IM in pts with IM intolerant CML in
CP and AP
- To evaluate the study of NL in pts who were previously intolerant to IM
-
Design:
95 pts in CML CP and 27 pts in CML AP entered study with IM intolerance
Post-hoc sub analysis of pivotal Phase II, open label, multicenter
400 mg NL BID
Continuous dosing unless toxicity
Dose escalation to 600mg BID at the discretion of the investigator if no response
IM intolerance defined as
o Pts w/o MCyR and who discontinued because of:
Persistent grade ¾ AE despite optimal supportive care
Persistent grade 2 AE related to IM despite optimal supportive care
 Persisting for 1 month
 Recurring > 3 months with requirement for dose reduction or discontinuation
Definition of Cross Intolerance:
o Occurrence of any drug related grade ¾ or persistent grade 2 during NL therapy that was
previously reported in the same patient while on IM


-
Results:
- The median dose intensity was closely approximate to the 800mg BID target
- Median dose interruption was short in comparison to median duration of therapy
- Cross intolerance AE between IM and NL were rare
- Approx. 1/3 of pts were IM intolerant due to hematologic AE
- Fewer hematologic AE were observed during NL tx
- Cross intolerance of NL and IM with regard to hematologic AE was infrequent
- No pts with CML AP discontinued NL due to hematologic AE
- Thrombocytopenia appears to be the only cross intolerance AE that led to discontinuation of NL tx
in some pts
- NL is an effective tx option for pts with IM intolerance
Poster #7012: Dasatinib or High Dose Imatinib for Patients with Chronic Myelogenous Leukemia
Chronic-Phase (CML-CP) Resistant to Standard-dose Imatinib: 2 Year Follow up Data from START-R
Authors: Philippe Rousselot, Thierry Facon, Ronald Paquette, Diedger Niederweiser, Eric Blackardt,
David Dejardin and Hagop Kantarjian
Resistance to IM is well recognized:
- 31% discontinue IM after 5 years
- 14% lose an established response or progress by 5 years
- 15% fail to achieve MCyr by 1st year
Dasatinib (DS) is 325% fold more potent than IM, 16 fold more potent than Nilotinib (NL) in vitro
Prior to DS 800 mg dose of IM was the primary option
Current DS dose for CML-CP is 100mg QD
Objective of Study: Evaluate DS 80 mg BID vs. high-dose (800mg) of IM in CML-CP post resistance to
400-600mg of IM QD.
Primary objective: MCyR at 12 weeks
Secondary objective: Overall rates of MCyR, CCyR and MMR
International, randomized, open label, phase II trial
Definition of IM resistance:
Primary Resistance – lack of CHR after 3 months, lack of CCyR after 6 months, or lack of MCyr (Ph+
cells .35%) after 12 months
Acquired Resistance – relapse after CHR or MCyr
Starting dose 70 mg DS BID dose escalation allowed for inadequate response or disease progression
after 12 weeks. Dose reduction allowed for toxicities
Starting Dose of IM was 800 mg QD, reduced to 600mg for toxicities (patients previously untreated at
that dose)
Minimum Follow-up 24 months (LPFV to database lock).
Study Assessments:
Time to treatment failure was defined as time form randomization to progression or end of treatment
(lack of response, drug intolerance, or discontinuation for any reason).
PFS (progression free survival) was defined as time from randomization until disease progression
(including discontinuation at progression prior to crossover) or death.
AEs (Adverse Events) were assessed continuously and graded according to NCI Common Toxicity
Criteria for Adverse Events v3.0
Results:
DS superior to IM 800mg QD post IM (400-600mg QD) failure
- CCyR DS was 44% vs. IM 18% P=0.0025
- MMR DS 29% vs. IM 12% P=0.028
- 24 months PFS DS 88% vs. IM 65% P=0.0012
- Demonstrated efficacy regardless of prior IM dose
DS 70 mg BID was well tolerated
- The current label dose of 100mg QD was proposed based on a subsequent phase II dose
optimization study showing similar efficacy with less frequent key side effects compared with
70 mg BID
Poster #7014: Dasatinib Efficacy by Dosing Schedule Across Individual Baseline BCR-ABL Mutations in
Chronic Phase Chronic Myelogenous Leukemia (CML-CP) After Imatinib Failure
Authors: Andreas Hochhaus, Martin C Muller, Jorge Cortes, Dong-Wook Kim, Yousif Matloub, Lynn
Ploughman and Timothy Hughes
Rationale:
- Ds is the most potent BCR ABL inhibitor
- IM resistance, suboptimal response and intolerance are clinical challenges
- Across a series of phase II multicenter trials with 2 year follow up (START program) DS
demonstrated durable efficacy in pts with CML resistant or intolerant to IM
- DS treatment responses have been observed in pts with all BCR ABL mutations, except for T315I
(note from CAS some other exceptions are emerging)
- In Phase II dose optimization, DS 100mg QD was highly efficacious in pts with CML CP resistant or
intolerant to IM, with less frequent key side effects
Objective:
To analyze the efficacy of four DS dosing regimens among pts with baseline BCR ABL mutations in the
phase III CA180-034 dose optimization trial. The four dosing regimens were: 100mg QD, 70 mg BID,
140 mg QD, and 80 mg BID.
Results:
Baseline characteristics:
581 of 662 treated pts. Had baseline mutation evaluation performed as well as 1-year cytogenetic
response data, and were included in the current analysis
Pts characteristics, including frequency of baseline BCR ABL mutations were balanced across the four
groups.
Efficacy:
- Overall response rates were similar across the four dose arms
- Response to DS were examined in pts with or w/o BCR ABL mutations identified after IM failure or
suboptimal response
- Efficacy was evaluated according to individual mutations:
o 43 different baseline BCR ABL mutations were identified
- Efficacy was seen in all pts with all mutations except T315I
- CHR rates were high across the four groups in patients with BCR ABL mutations
Conclusions:
- DS is highly efficacious in pts with CML CP with baseline BCR ABL mutations and resistance,
suboptimal response or intolerance to IM
- MCyR to DS were seen in all of the baseline mutations identified, except T315I
- Rates of MCyR (59%) and CCyR (43%) for DS 100mg QD were similar to those for the other dosing
schedules testing (including 70 mg BID) in these pts.
- DS 100 mg QD was associated with an MCyR rate of 63% and a CCyR rate of 50% in pts with baseline
mutations in the P-loop
- Durability of MCyR and CCyR and PFS at 1 year for DS 100mg QD in pts with any baseline BCR ABL
mutation were favorable and similar to those for the other dosing schedules tested.
# 7015 Dasatinib Lack of Cross Intolerance to Imatinib in Patients with Chronic Myelogenous
Leukemia Chronic Phase (CML CP) Intolerant to Imatinib: a Retrospective Analysis of Safety
Authors: H Jean Khoury, Stuart L Goldberg, Michael J Mauro, Richard M Stone, Yousif Matloub, TsiTsang Chen, and Francois Guilhout
Rationale:
- DS is the most potent BCR ABL inhibitor and is structurally unrelated to IM
- DS is associated with high remission rate and durable responses in pts with CP CML resistant or
intolerant to IM
- Intolerance of IM leads to drug discontinuation in 5% of pts with CML CP (IRIS trial)
- The most common sighted AEs to IM reported during IM treatment included cytopenias, fluid
retention, GI disturbances, rash and musculoskeletal AEs
Objective:
- To assess the tolerability of DS in IM intolerant pts enrolled in DS clinical trials in CML-CP
Methods:
- Pts were pooled from two multicenter clinical trials
- Pts were included in the analysis if they had CML CP, IM intolerance defined as  grade 3 non
Hematologic toxicity or grade 4 hematologic toxicity that persisted for >7 days
- Key exclusion criteria for both trials included uncontrolled or significant cardiovascular diseases and
history of a significant bleeding disorder unrelated to CML.
- DS dosing was on of four schedules: 70 mg BID, 100 mg QD (the current dosing schedule in CML CP)
50 mg BID or 140 mg QD
- Dose escalation was allowed for inadequate response
- Dose interruption or reduction was allowed following drug related grade  2 non-hematologic
toxicity or grade  hematologic toxicity.
Cross Intolerance:
- Determined in this analysis by:
- The recurrence of specific grade ¾ AEs during DS therapy that had previously been documented
during IM therapy
- DS discontinuation following the same grade ¾ AE
Assessments:
- Standard efficacy assessments were used for classification of complete hematologic response
(CHR) major cytogenetic response (MCyr) and CCyR
- Progression was defined as increasing WBC count, loss of CHR or MCyr, confirmed
accelerated/blast phase, or death
- AEs and other symptoms occurring during DS treatment we graded according to the National
Cancer Institute Common Terminology Criteria for AEs v3.0
Results:
- Pt characteristics
- 271 pts with IM intolerance CML CP were included in the analysis
- The duration of IM treatment was < 1 year in 58% of pts.
- 92% of pts had received IM 400 or 600 mg/day
- IM intolerance was related to non-hematologic toxicity in 225 (83%) pts and hematologic toxicity in
46 (17%) pts.
- The exact cause of IM intolerance was not available in 15% of the pts with non-hematologic
toxicity and 3 pts with hematologic toxicity
DS Treatment:
- Median duration of DS therapy in this analysis was 12.0 months (range 0.0-30.1 months)
- At last follow up 58% of these IM intolerant pts were still receiving DS treatment
- 53% of the pts had received 70 mg BID of DS and 16% had received DS 100mg QD
Conclusions:
- In the 271 pts with CML CP and IM intolerance cross intolerance to DS was uncommon
- Rates of DS discontinuation following recurrence of IM associated AEs were low:
o 1& of pts with non-hematologic intolerance
o 14% of pts with hematologic intolerance
- 4% of pts experienced a grade ¾ non-hematologic AE recurrence in DS
o Fluid retention in IM did not predict the development of pleural effusions in DS
- Recurrence of hematologic toxicity
o Was unrelated to dose
o Did not frequently lead to discontinuation
o May reflect effective inhibition by DS of BCR ABL driven hematopoiesis, i.e. DS antileukemic activity
- DS 100 mg QD is associated with minimal cross intolerance and is the recommended dose for pts
with CML CP
-
DS has durable efficacy in pts with IM intolerance
#7018 A Phase I study of INNO 406 in Patients with Advanced PH+ Leukemia’s who are Resistant or
Intolerant to IM and May Have Also Failed Second-Generation TKI’s
Authors: Javier Pinilla-Ibarz, Hgop M Kantarjian, Jorge E Cortes, Arnon Nagler, Andreas Hochhaus,
Dan Jones, Philip le Coutre, Shinya Kimura, Eric Poma, Lyon Gleich, Oliver G. Ottmann
Abstract:
Rationale: Inno-406 is an oral dual ABL/Lyn KI, which is up to 55 times more potent than IM.
Numerous BLC ABL mutant proteins are sensitive to INNO 406 in vitro including the F317L mutant
(Personal note from CAS: important note, this mutant is not sensitive or at least only very mildly
sensitive to DS)
Methods: Phase I study in Ph+ with resistance or intolerance to IM who may have also failed 2 nd
generation TKI’s treated with INNO 406 orally at doses ranging from 30 mg QD to 480 mg BID. Part I,
the dose finding portion of the study was completed. And additional ten (10) pts were enrolled on
the expansion phase (part 2) of the study at the MTD of 240mg BID.
Results: 56 pts enrolled, 32 pts w/ CML CP, 8 pts w/ CML AP and 7 pts w/ CML BP. 9 pts with Ph+
ALL. Pts included in the part I included pts who were previously treated with IM (n=12), IM + NL or
DS (n=26) or IM + NL + DS (n= 8). In part II previous treatment in this group was: IM only (n=5) IM +
NL or DS (n=3) or IM + NL + DS (n=2). Common mutations on study entry included Y253H (n=4), G350E
(n=4), F317L (n=3), and T315I (n=2). Currently 14 pts remain on study. Cytogenetic responses, CCyR
were seen in 8 pts, including in a CML CP pts who had failed both IM and DS. Drug related grade ¾
adverse events included: reversible elevations of liver transaminases and bilirubin,
thrombocytopenia, and acute renal failure. No grade 34 pleural effusions, peripheral edema, or
pericardial effusions were seen and a minimal mean QTc effect was observed. No drug related
severe neutropenias were seen.
Conclusions:
Inno-406 has generated CR in CML pts that have failed one or more TKI’s with all responses
occurring at a dose of 240 mg BID or lower
- INNO-406 is well tolerated with few Grade 3 and only one Grade 4 drug related AE seen at the
recommended phase II dose of 240mg BID
- There is no evidence of fluid retention and a very low level of neutropenia seen with INNO-406
- A phase II study is planned in pts who have previously received IM and DS or NL
-
Efficacy of Dasatinib in Patients with Previously Untreated Chronic Myelogenous Leukemia in Early
Chronic Phase
Authors: G. Borthakur, H. Kantarjian, S. O’Brien, D. Jones, C. Koller, C. Nicaise, G. Garcia-Manero,
A. Ferrajoli, J. Cortes
Abstract: DS is a multi-targeted TKI of BCR ABL and SRC w. significant activity in pts with CML CP
resistant or intolerant of IM. Phase II trial to study efficacy and safety of DS in pts with previously
untreated CML CP
Methods: Preliminary objective was to estimate the proportion of pts attaining major molecular
response at we months. Pts with previously untreated CML CP were eligible and received DS 100 mg
daily randomized to either 50 mg BID or 100mg QD.
Results: 41 pts enrolled (21 on QD schedule and 19 on BID schedule). @ 12 months 32% of evaluable
pts (8/25) had achieved a major molecular response. Responses are similar in both treatment
groups. Grade ¾ non-hematologic toxicity (regardless of causality) included fatigue 5%, headache 3%
and rash 3%. Pleural effusion occurred in 5 (13%) of pts – all grade 1 and 2. Grade ¾ hematologic
toxicity (transient) were thrombocytopenia’s 10%, neutropenias 5%, and anemia 3%. Median follow
up of 18 months, 18 pts required treatment interruption and dose reduction. The actual median
dose for all pts was 100mg. There is no significant grade ¾ treatment toxicity by treatment
schedule.
Conclusions:
- DS induced rapid CCR in most pts.
- Most pts are able to receive the targeted dose
- No significant difference between schedules
- CCR faster than with standard dose IM
- Molecular responses comparable with high-dose IM @ 18 months
Imatinib use in Chronic Phase CML in Clinical Practice: The UNIC Study
Authors: Juan Louis Steegmann, MD, Mauricette Michallet, MD, Enrica Morra, MD, David Marin, MD,
Gert Ossenkoppele, MD, Gregor Verhoef, MD, Thomas Kuhr, MD, Matas Bjoreman, MD, Muriel Sterckx,
MD and Karin Cerri, Msc. Participating Countries: Austria, Belgium, France, Italy, Netherlands,
Spain, Sweden and the UK
Abstract:
Rationale: IM is widely used to treat CML. The unmet needs in CML study assess real-life treatment
of CML
Methods: This cross sectional study with retrospective chart review of pts currently treated for
CML/Ph+ ALL in 8 European countries (enrolled Sept 06 – Mar 07), assessed proportions of IM treated
pts and those with resistance/intolerance (primary aims). A secondary aim was to describe dosing
patterns. A registry was collected of adults treated for CML/Ph+ ALL at participating centres. Case
report forms (CRF) were completed for eligible pts. Data was collected at the most recent visit and
retrospectively via chart review.
Results: CRF’s were analyzable for 1492 pts in CML CP, of whom 97% had received IM. Of these,
44.6% were IM resistant and/or intolerant (as reported in the medical chart if resistance/toxicity led
to a change in or discontinuation of IM use) at some time since IM initiation. 20% stopped and did
not restart IM during the study period. 23% stopped IM temporarily due to toxicity (median duration
22 days), of whom ~30% had >1 such interruption. The most common increase was 400 to 600mg
(33%); most common decrease was 400 60 300mg (39%). 16% of increases and 14% of decreases were
both to and from doses <400mg. of the 520 pts with  dose increase, 17.5% were IM resistant just
prior to dose change, of whom 63% were resistant at last observation. Median last IM dose was
higher in IM-resistant (600mg; N=149) vs. non-resistant (400mg N= 1205) pts. 41% of IM resistant pts
had received doses  400mg. Of pts with IM dose increases to 600 and 800mg, 22% (62/284) and 32%
(36/112) had a toxicity post increase, respectively.
Conclusions:
- Median last IM dose was 600mg in IM resistant versus 400mg in non-resistant pts.
- 41% of IM treated CML CP pts had a dose increase
- 33% of IM treated CML CP pts had a dose decrease
- 13% of pts received doses of IM < 400mg
- Of the pts who had IM dose increase to 600 or 800 mg, 88% and 96% respectively, of those who did
not have a CCyR before the dose increase did not have a Cyr after the increase.
A notable portion of IM treated CML CP patient in this large observational study needed dose
modification. Some pts may be receiving suboptimal IM doses. IM resistant pts received higher IM
doses.