1102 The Majority of Chronic Myeloid Leukaemia Patients Who Cease Imatinib after Achieving a
Sustained Complete Molecular Response (CMR) Remain in CMR, and Any Relapses Occur Early
Saturday, December 6, 2008
Hall A (Moscone Center)
David M Ross1*, Andrew Grigg2*, Anthony Schwarer2, Christopher Arthur2, Kerryn Loftus3*, Anthony K Mills2*,
Robin Filshie2*, Ruth Columbus2*, John Reynolds2*, John F Seymour, MB, BS, PhD, FRACP4*, Susan
Branford1* and Timothy Hughes1
1Institute of Medical & Veterinary Science, Adelaide, Australia
2Australasian Leukaemia & Lymphoma Group, Australia
3Novartis Pharmaceuticals, Australia
4Dept of Haematology, Peter MacCallum Cancer Institute, Victoria, Australia
After 5 years of imatinib treatment 40-50% of chronic myeloid leukaemia (CML) patients will have stable
undetectable BCR-ABL by real-time quantitative RT-PCR (RQ-PCR) using strict sensitivity criteria (‘complete
molecular response', CMR). Many patients who stop imatinib in CMR will relapse, but small numbers have been
reported with sustained CMR after imatinib withdrawal. We designed a non-randomised prospective Phase 2
study of imatinib withdrawal in adult chronic phase CML patients in CMR for ≥2 years
(ACTRN012606000118505). Patients were treated in multiple centres around Australia, and RQ-PCR for BCR-
ABL was performed centrally: monthly for the first year after imatinib withdrawal, and 2-monthly in the second
year. Molecular relapse was defined as a single PCR result above the level of major molecular response (MMR)
or any two consecutive positive results. Molecular relapse was treated with imatinib and patients were monitored
monthly for 12 months to assess response to re-treatment. Patients were enrolled in two cohorts: imatinib de
novo (IM only, n=5) and imatinib after prior interferon therapy (IFN-IM, n=13). The median duration of prior IFN
was 39 months. Both cohorts continue to accrue. For all 18 patients the median age at study entry was 58
years; 44% were male. The median duration of imatinib treatment was 60 months (R40-89). The Kaplan-Meier
estimate of the rate of sustained CMR after 12 months off treatment was 67% (95% confidence interval 40-85%,
see Figure). Ten of 13 IFN-IM patients (77%) remain in CMR, and 7 of these have been in CMR for at least 12
months without treatment (maximum 23 months). The median follow-up in the IM only patients is currently only 7
months (R1-15), and 3/5 remain in CMR. All molecular relapses in both groups have occurred within 5 months of
stopping imatinib. The median duration of prior imatinib treatment was not different in the 5 patients with loss of
CMR (76 months) versus those in stable CMR (60 months; p=0.59). Among the 5 patients with loss of CMR the
median time to molecular relapse was 3 months (range 2-5 months). Two relapsing patients lost MMR, and 3
had detectable BCR-ABL mRNA below this level. No patient has experienced haematological relapse or
developed a kinase domain mutation. At last follow-up all 5 relapsing patients had regained CMR after a median
of 5 months of re-treatment with imatinib. Patient-specific DNA Q-PCR assays were developed to test whether
minimal residual disease (MRD) was detectable in genomic DNA in patients in CMR defined by RQ-PCR for BCR-
ABL mRNA. Results are available for 6 patients, 3 of whom have relapsed. One relapsing patient had BCR-ABL
DNA detected prior to imatinib withdrawal. In the remaining 2 relapsing patients BCR-ABL DNA was detected
after imatinib withdrawal, but 2-3 months prior to the detection of BCR-ABL mRNA by RQ-PCR. BCR-ABL DNA
increased by at least 1-log between the time of the first positive result and the detection of molecular relapse by
RQ-PCR. The 3 patients in stable CMR had no detectable BCR-ABL DNA. In conclusion, with close molecular
monitoring imatinib withdrawal in stable CMR appears to be safe: currently all patients are either in stable CMR
off treatment or back in CMR after re-treatment. Withdrawal of effective treatment outside the setting of a clinical
trial is not recommended. Monitoring of MRD by genomic DNA Q-PCR was able to detect molecular relapse prior
to mRNA RQ-PCR, and shows promise for the prospective identification of patients at high risk of relapse. There
is an apparent dichotomy of response between early molecular relapse and durable CMR, at least in patients
treated with imatinib after IFN. It is too early to identify clinical or laboratory factors (such as prior IFN treatment)
that may influence the probability of sustained CMR without treatment.
International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained
Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in
Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated
with Imatinib (IM)
Monday, December 8, 2008: 8:15 AM
Halls B and C (Moscone Center)
Stephen G O'Brien, MD, PhD1*, François Guilhot, MD2, John M Goldman, DM, FRCP3*, Andreas Hochhaus,
MD4, Timothy P Hughes, MD5*, Jerald P. Radich, MD6*, Marc Rudoltz, MD7, Jeiry Filian7*, Insa Gathmann, M.Sc.
8*, Brian J. Druker, MD9 and Richard A. Larson, MD10
1Department of Haematology, University of Newcastle, Newcastle, United Kingdom
2Clinical Investigational Centre INSERM 802, CHU Poitiers, Poitiers, France
3Department of Hematology, Imperial College London, Hammersmith Hospital, London, United Kingdom
4Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany
5Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia
6Fred Hutchinson Cancer Research Ctr., Seattle, WA
7Oncology, Novartis Pharmaceutical, Inc., Florham Park, NJ
8Novartis Pharma AG, Basel, Switzerland
9Oregon Health & Science University Cancer Institute, Portland, OR
10University of Chicago, Chicago, IL
Background: Based on results from the IRIS trial, IM is the standard of care for pts with newly diagnosed CML-
CP. This report presents the 7 yr data update of IRIS to assess long term outcome, response rate, and safety in
pts on primary IM therapy.
Methods: 553 pts were randomly assigned to IM and evaluated for hematologic, cytogenetic and molecular
responses, discontinuations/cross-over reasons, event-free survival (EFS), progression to accelerated-phase
(AP) or blast crisis (BC) and OS. Events for EFS were defined as the first occurrence of any of the following
during treatment: death from any cause, progression to AP/BC, loss of a complete hematologic response or
major cytogenetic response (MCyR), or an increasing white blood cell count to > 20 x 109/L. After
discontinuation of study treatment, pts were followed only for OS.
Results: At 7 yrs, the estimated EFS was 81%, freedom from progression (FFP) to AP/BC was 93%, and the
estimated OS was 86%. The best observed rates for MCyR and complete cytogenetic response (CCyR) were
89% and 82%, respectively. A total of 317 (57%) of all randomized pts remained on IM per protocol and were in
CCyR. The estimated rates of progression to AP/BC from yrs 1 through 7 are 1.5, 2.8, 1.6, 0.9, 0.5, 0, and
0.4%, respectively, with one pt progressing to AP/BC between yrs 6 and 7. Yearly event rates are 3.3%, 7.5%,
4.8%, 1.7%, 0.8%, 0.3% and 2% (5 events occurred in the 7th yr: 3 unconfirmed loss of MCyR, 2 deaths). Of
the 456 pts who achieved CCyR, 79 (17%) subsequently lost CCyR; 25 remained on IM (19 pts regained CCyR,
of whom 6 responded to an increase in IM dose; 6 pts remained in MCyR without dose escalation). A total of 15
pts (3%) who achieved CCyR on IM progressed to AP/BC during study treatment, typically during the 1st year
after achievement of CCyR; 3 CCyR pts progressed to AP/BC after the 2nd year. A total of 332 (60%) pts
remain on IM on protocol at the 7-yr data cut-off. Reasons for discontinuation or crossover include: 5% adverse
events/safety, 15% lack of efficacy/progression, 3% bone marrow transplant, 2% death, and 15% other (protocol
violation, withdrawal of consent or lack of renewal of consent, lost to follow-up, administrative) reasons. Between
yrs 6 and 7, 17 pts (3%) discontinued IM for the following reasons: adverse events (n=3), death (n=2; 1 CML-
related), unsatisfactory therapeutic effect (n=7; 1 progression to AP/BC, 4 unconfirmed loss of MCyR, 2
unconfirmed loss of CCyR), protocol violation (n=1), and withdrawal of consent (n=4).
Molecular response (MR) assessment was required per the IRIS protocol only in pts who had achieved CCyR.
However, MR was measured routinely in 98 pts treated in Australia/New Zealand and Germany (sub-study) at
baseline and every 3 mo through 72 mo, and other sites contributed assessments if available. Of the total IRIS
IM cohort, 476 pts had at least one PCR measurement. MMR was defined as a ratio of BCR-ABL/control
transcripts of ≤ 0.1% according to the International Scale.
Table 1: MR over time: BCR-ABL/control gene transcript levels (as % of available samples)
All available samples
Sub-study samples
Time-points
(mo)
n
>10%
> 1.0 - ≤10%
> 0.1 -
≤ 1.0%
≤ 0.1%
(MMR)
n
≤ 0.1%
(MMR)
3
174
25%
39%
24%
13%
87
8%
6
258
15%
17%
35%
33%
86
28%
12
305
9%
12%
30%
50%
81
47%
18
253
6%
10%
19%
65%
70
63%
48
238
6%
9%
10%
75%
66
82%
60
273
3%
4%
8%
85%
71
90%
72
210
2%
3%
9%
86%
57
88%
The MMR rates at 12 and 48 mo for all available samples are consistent with the reported rates of 53% and
80%, respectively, noted in a subset of pts with CCyR (Druker et al, NEJM, 2006) and similar to the unselected
sub-study data. Additionally, MMR responses at 12 mo are similar to the recently reported TOPS trial (Cortes et
al, EHA 2008). Between yr 6 and 7, serious adverse events suspected to be related to IM were reported in 9 pts,
resulting in treatment discontinuation in 3 pts. No new safety issues were identified.
Conclusions: Responses with IM therapy remain durable with estimated 7 yr rates of FFP to AP/BC 93%, EFS
81%, and OS 86%. Only 1 patient progressed between yrs 6 and 7. The safety profile is unchanged and
confirms a favorable risk-benefit ratio in CML-CP. Long-term follow-up of pts who continue to respond to IM
demonstrate an MMR rate of 85-90% at 5-6 years. These results demonstrate increasing suppression of CML
over time in patients who continue to receive imatinib.
185 Cytogenetic and Molecular Response to Imatinib in High Risk (Sokal) Chronic Myeloid Leukemia
(CML): Results of An European Leukemianet Prospective Study Comparing 400 Mg and 800 Mg Front-
Line
Monday, December 8, 2008: 8:00 AM
Halls B and C (Moscone Center)
Michele Baccarani1, Fausto Castagnetti2*, Bengt Simonsson3*, Kimmo Porkka4*, Ibrahim C. Haznedaroglu5*,
Arnon Nagler6, Francesca Palandri2*, Giovanna Rege Cambrin7*, Luciano Levato8*, Fausto Palmieri9*,
Elisabetta Abruzzese10, Ugur Özbek11*, Veli Kairisto12*, Hans Bostrom3*, Johann Lanng Nielsen13*, Henrik
Hjorth-Hansen14*, Ole Weis-Bjerrum15*, Nicoletta Testoni2*, Giovanni Martinelli16*, Fabrizio Pane, MD17,
Giuseppe Saglio7* and Gianantonio Rosti2*
1Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy
2Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy
3Hematology Unit, Uppsala University, Uppsala, Sweden
4Helsinki University Central Hospital, Helsinki, Hematology Research Unit, Finland
5Hematology, Hacettepe University, Ankara, Turkey
6Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
7Internal Medicine and Hematology, Università di Torino - Ospedale San Luigi, Orbassano, Italy
8Hematology Unit, Catanzaro, Italy
9Hematology Unit, Avellino, Italy
10S. Eugenio Hospital, Rome, Italy
11Instanbul University, Instanbul, Turkey
12Turku University Central Hospital, Department of Medicine, Turku, Finland
13Aarhus University Hospital, Aarhus, Denmark
14St Olavs University Hospital, Trondheim, Norway
15Hematology Unit, Rigshospitalet, Copenhagen, Denmark
16Department of Hematology and Oncological Sciences, Seragnoli Institute, University of Bologna, Bologna, Italy
17A.F. di Oncologia Ematologica Diagnostica, Azienda Ospedaliera, Napoli, Italy
Sokal risk formulation was elaborated 25 years ago, based on very simple factors (age, spleen size, platelet
count, and percentage of myeloblasts in the peripheral blood), based on patients treated with conventional
chemotherapy. In spite of that, Sokal risk score is still the major prognostic factor for response to treatment with
the tyrosine kinase inhibitor, Imatinib mesylate (IM). Since several preclinical, pharmacokinetic and clinical
studies suggested that the therapeutic efficacy of IM may be concentration/dose–dependent, we assigned
prospectively 217 adult patients with Ph pos CML, Sokal high risk (SHR), to be treated front line with IM 400 mg
or 800 mg (Clin.Trials Gov. NCT00514488), comparing the cytogenetic and the molecular response rates at 3,
6, and 12 months. Cytogenetic response was evaluated by chromosome banding analysis (CBA) of marrow
metaphases, and by FISH analysis of marrow cells in case of insufficient metaphase number. Molecular
response was evaluated by RT-Q-PCR (PB), according to the international scale. The results are shown in
Table 1. No difference between the two arms was significant at any time point. In the 400 mg arm, the median
daily dose of IM was 400 mg, with 87% of patients receiving 350 to 400 mg. In the 800 mg arm, the median daily
dose of IM was 720 mg, with 63% of patients receiving 600 to 800 mg. The CCgR rate was 86%, vs 66% in the
patients who received a median daily dose of 600 to 800 or less than 600 mg daily, respectively (p=0.013). With
a median follow up of 31 months (range 1-49 months), progression-free and overall survival are higher than
90% in both arms. Based on an intention-to-treat analysis, this study did not show a significant benefit of 800 mg
over 400 mg in SHR patients, but the patients who could comply with the high dose had a better cytogenetic
outcome.
3 months
6 months
12 months
400
800
400
800
400
800
No. of pts
109
108
109
108
109
108
Dropouts(1)
4%
4%
5%
7%
5%
8%
D/C adverse events
1%
2%
4%
4%
4%
7%
Failure(2)
1%
1%
9%
10%
16%
15%
CCgR(3)
19%
25%
49%
52%
58%
64%
MolR>3.0 log(4)
7%
12%
25%
31%
33%
40%
MolR>4.5 log(4)
1%
2%
3%
9%
10%
19%
Transcript level (median)
2.085
1.122
0.378
0.108
0.084
0.036
(1)Refusal, or lost to follow-up, or protocol violations
(2)Failure was defined according to the ELN recommendations (Baccarani et al, Blood 2006;108:1809-1920)
(3)No Ph pos metaphases out of at least 20 marrow cell metaphases, by CBA, or < 1% BCR-ABL positivity out of
at least 200 marrow cells, by FISH
(4)BCR-ABL:ABL < 0.10 and < 0.005 by RT-Q-PCR, converted to the International Scale.
Table 1: Summary of cytogenetic and molecular results. All percentages are calculated based on all randomized
patients, according to the intention-to-treat principle. p-values are > 0.10 for all comparisons.
187 Is It Possible to Stop Imatinib in Patients with Chronic Myeloid Leukemia? An Update from a
French Pilot Study and First Results from the Multicentre « Stop Imatinib » (STIM) Study
Monday, December 8, 2008: 8:30 AM
Halls B and C (Moscone Center)
Francois-Xavier Mahon1*, Francoise Huguet, MD2*, Francois Guilhot, MD3, Laurence Legros, MD, PhD4*,
Franck E Nicolini, MD, PhD5, Aude Charbonnier6*, Agnes Guerci, MD7*, Delphine Rea, MD, PhD8*, Bruno R.
Varet, MD9, Martine Gardembas, MD10*, Joelle Guilhot3*, Gabriel Etienne11*, Noel-Jean Milpied, MD, PhD12,
Emilie Aton13*, Josy Reiffers11* and Philippe Rousselot14*
1Hématopoïèse leucémique, Université Victor Segalen CHU de Bordeaux, Bordeaux, France
2Service d'Hématologie, Hôpital Purpan, Toulouse, France
3Cic-P 802 Inserm, CHU de Poitiers, Poitiers, France
4Service d'Hématologie, Hôpital de l'Archet, Nice, France
5Hematology Department, Hospital E. Herriot, Lyon, France
6Institut Paoli Calmette, Marseille, France
7Service d'Hématologie, CHU Brabois, Nancy, France
8Service Des Maladies Du Sang, Hôpital Saint Louis, Paris, France
9Hematology Dept., Paris Descartes Univ. Necker Hospital, Paris, France
10Haematology, CHU Angers, Angers, France
11Institut Bergonié, Bordeaux, France
12Service des maladies du sang, Hopital Haut Leveque, Pessac, France
13Hopital Haut Leveque - Pessac, Bordeaux, France
14Centre André Mignot, Versaille, France
Imatinib (IM) has greatly improved survival rates in chronic myeloid leukemia (CML). However, all patients (pts)
must continue treatment for an unknown period of time. A pilot study of the first pts who discontinued IM therapy
was previously reported (Rousselot et al. Blood 2007;109:58–60). The new, multicentre « Stop Imatinib » (STIM)
study was started in July 2007. The aim of this study is to evaluate in a larger cohort the persistence of complete
molecular remission (CMR) after stopping IM, and to determine the factors that could influence the persistence
of CMR. The criteria for inclusion were IM treatment for at least 3 years and sustained CMR. Sustained CMR was
defined as BCR-ABL/ABL levels below a detection threshold corresponding to a 5-log reduction (undetectable
signal using RQ-PCR) for at least 2 years. Molecular relapse, defined as RQ-PCR positivity, was taken into
account if confirmed in two successive assessments. In cases of molecular relapse, pts were re-treated with IM
at 400 mg dailyIn the pilot study, 7 out of 15 pts relapsed within 6 months, but CMR was re-attained in all cases
after IM was re-started. The other 8 pts (4 male, 4 female) are still in CMR, with a median follow up of 37 months
(range 26–49 months) after IM discontinuation. All pts were pre-treated with interferon-alpha (IFN) and most
responded to IFN before IM treatment.
The STIM study included 50 pts from 18 centres (20 male, 30 female), with a median age of 62 years (range 32–
81 years). Of these, 25 pts had received no pre-treatment with IFN. By July 2008, 34 pts had a follow up ≥ 6
months. Eighteen pts relapsed within the first 6 months: 3 pts in month 2 (M2), 8 pts in M3, 4 pts in M4, and 3 pts
in M5. One patient relapsed after more than 6 months (M8). Among the 19 pts who relapsed, 11 were not IFN
pre-treated and 8 were IFN pre-treated (relapse rate 44% vs 32%). Ten IFN pre-treated pts with follow up ≥ 6
months have not relapsed (M12 in 2 pts, M10 in 5 pts, M8 in 1 pt, M7 in 2 pts), and 5 pts with follow up ≥ 6
months who were not IFN pre-treated have not relapsed (M12 in 1 pt, M10 in 1 pt), M8 in 1 pt, M6 in 2 pts).
These studies confirm that CMR can be sustained after discontinuation of IM, particularly in pts pre-treated with
IFN with a long follow-up (pilot study). Among pts in the STIM study who were not pre-treated with IFN, more than
half have not relapsed, and 20% have reached a follow-up ≥ 6 months and not relapsed. Updated data will be
presented but we conclude that it is possible to stop treatment in pts with sustained CMR, even in those treated
with IM as a single agent.
447 Imatinib (IM) Pharmacokinetic (PK) Exposure and Its Correlation with Clinical Outcome in Patients
with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) for 400 Mg and 800 Mg Daily Doses
(Tyrosine Kinase Dose Optimization Study [TOPS])
Monday, December 8, 2008: 2:00 PM
2009-2011-2022-2024 - West (Moscone Center)
François Guilhot, MD1, Timothy P Hughes, MD2*, Jorge Cortes, MD3, Yanfeng Wang, PhD4*, Michael Hayes,
PhD4*, Anthony Gichangi, PhD5*, Brian J. Druker, MD6 and Michele Baccarani, MD7*
1Clinical Investigational Centre INSERM 802, CHU de Poitiers, Poitiers, France
2Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia
3M.D. Anderson Cancer Center, Houston, TX
4Novartis Pharmaceuticals, East Hanover, NJ
5Novartis Pharmaceuticals, Basel, Switzerland
6Oregon Health & Science University Cancer Institute, Portland, OR
7Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy
Background: Correlation between IM plasma level and clinical response has been previously reported [Larson et
al., Picard et al.]. TOPS is an open-label, randomized, multicenter Phase III study investigating whether 800 mg
of IM (400 mg twice daily) results in an improved efficacy compared with 400 mg daily IM in newly diagnosed,
previously untreated CML-CP. This analysis reports IM trough plasma levels (Cmin) at both doses and their
correlation with clinical response and safety parameters.
Methods: IM PK trough samples were collected at time 0 (predose), and following 1, 6, 9, and 12 month
treatment for both 400 mg/day (mg/d) and 800 mg/d arms. Plasma concentrations of IM and CGP74588 (major
metabolite) were determined by a validated LC/MS/MS (liquid chromatography and tandem mass spectrometry)
method. Correlation of IM exposure with clinical response (major molecular response [MMR] rates and time to
first MMR) was assessed by grouping patients into quartiles based on their measured IM Cmin levels in month 1.
For correlation with frequency of adverse events [AEs], an average Cmin (aCmin) over 12 months corrected for
dose intensity was used for the analysis. Correlations were assessed for the entire evaluable population and for
each dose group separately.
Results: IM PK exposure was proportional to dose and stable over time. For the 400 mg/d dose (n=78-87), the
median IM Cmin values at month 1, 6, 9, and 12 were 1190, 1060, 1210, and 1295 ng/mL, respectively; and for
the 800 mg/d dose (n=148-167) the corresponding Cmin values for each month were 2720, 2340, 2170, and
2150 ng/mL, respectively. The intra-patient variability (CV%) was low and similar between the 400 mg/d and 800
mg/d doses, 25% and 27%, respectively. The inter-patient variability (CV%) was 38% for 400 mg/d and 58% for
800 mg/d. Despite this inter-patient variability there was a strong correlation between IM Cmin at month 1 (Table
1) and time to MMR or MMR at 3, 6, 9 and 12 months.
Table 1: MMR rates over 12 months based on month 1 IM Cmin quartiles for evaluable patients with PK data
Month of treatment (No. of evaluable patients)
MMR Rate* (%)
Relative benefit
(Fishers Exact Test p-value)
IM Cmin Q1
<1165 ng/mL
IM Cmin Q2-Q3
1165-3180 ng/mL
IM Cmin Q4
>3180 ng/mL
Q2-Q3 vs Q1
Q4 vs Q1
Month 3 (218)
0/54 (0%)
15/108 (14%)
10/56 (18%)
NA (0.0027)
NA (0.0013)
Month 6 (208)
8/51 (16%)
38/103 (37%)
22/54 (41%)
2.35 (0.0084)
2.60 (0.0052)
Month 9 (212)
21/57 (37%)
60/103 (58%)
29/52 (56%)
1.58 (0.013)
1.51 (0.0561)
Month 12(214)
21/56 (38%)
62/107 (58%)
30/51 (59%)
1.55 (0.0142)
1.57 (0.0338)
*No. of patients achieving MMR/total number of patients evaluable at each visit
Based on the evaluable population at month 12, patients with higher Cmin at month 1 (>1165 ng/mL, Q2-Q4)
achieved MMR faster than patients with lower Cmin (<1165 ng/mL, Q1) (P=0.0149). The MMR rate at 12 months
was 58% for Q2-Q4 group and 38% for Q1 group (P=0.0263). In the 400 mg/d group, the MMR rate at month 12
was 24% for patients with Cmin below 851 ng/mL (Q1 for 400 mg/d), compared to 56% for patients with Cmin
above 851 ng/mL (Q2-Q4; P=0.0207). In the 800 mg/d arm, the overall MMR at 12 month was 50%, and no
significant differences were observed between different Cmin quartiles, although it should be noted that the
majority of patients (88%) at this high dose level achieved a Cmin above 1165 ng/mL as compared with 52% for
the 400 mg/d group. Using aCmin over 12 months as a rough estimate of exposure including dose changes, a
slightly higher incidence of all grade AEs for the most frequently reported AEs such as rash, diarrhea, fatigue,
and all cause edema, was observed in patients in the highest quartile but no significant differences in the
frequency of grade 3/4 AEs were observed.
Conclusion: In TOPS, IM plasma trough level was proportional to dose and stable over time despite a high inter-
patient variability which may have been attributable to dose changes. Patients with a IM Cmin in the lowest
quartile showed a lower MMR rate at 12 months, whereas patients in the highest aCmin quartile showed a higher
frequency of all grades of some AEs. The TOPS trial confirms previous observations that IM Cmin of
approximately <1000 ng/mL are associated with poorer outcomes. Monitoring IM levels can provide an added
benefit to CML patients on IM to achieve the best clinical outcomes.
445 Significance of Rising Levels of Minimal Residual Disease in Patients with Philadelphia
Chromosome-Positive Chronic Myelogenous Leukemia (Ph+ CML) in Complete Cytogenetic
Response (CGCR)
Monday, December 8, 2008: 1:30 PM
2009-2011-2022-2024 - West (Moscone Center)
Hagop M Kantarjian1, Jianqin Shan2*, Dan Jones2, Susan O'Brien2*, Mary Beth Rios2, Elias Jabbour2* and
Jorge Cortes2*
1The University of Texas M. D. Anderson Cancer Center, Houston, TX
2M.D. Anderson Cancer Center, Houston, TX
Background. Patients with Ph+ CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for
response by quantitative polymerase chain reaction (QPCR) studies for minimal molecular disease. The clinical
significance of rising levels of QPCR in CGCR is uncertain. Study Aims. To evaluate the relevance of increases
of QPCR levels in patients with CML in CGCR on therapy. Study Group and Methods. Of 258 patients on
imatinib therapy for newly diagnosed CML, 116 patients in durable CGCR on imatinib therapy for at least 18
months had significant QPCR increases (documented at least twice) as defined by literature reports. These
were analyzed by the achievement of major molecular response (MMR; QPCR < 0.05%), and by the degree of
QPCR increase. Results. The outcome of patients by disease status (still in MMR vs. loss of MMR vs. never in
MMR) and by the QPCR level increase are shown in the Table. Only 13 of 116 patients (11%) with significant
QPCR increases had CML progression; 11 of them were among 44 patients (25%) who either lost a MMR or
never had a MMR, and had > 1 log increase of QPCR. The 5-year survival of all 116 patients was 92%,
suggesting the minimal relevance of QPCR increases in patients in CGCR. Conclusion. Most patients with
significant QPCR increases remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have > 1
log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL
kinase domain and considered for investigational therapeutic interventions. Allogeneic stem cell transplant
should not be considered in view of the excellent survival.
Outcome of Patients in CGCR by QPCR Increases
Disease Status
QPCR Log increase
No. Patients
CML Progression
Median follow-up from QPCR increase in months (range)
Persistent MMR
Any
28
0
36 (3-62)
Loss of MMR
>0.5-1
12
0
34 (14-59)
>1-2
25
3
31 (6-52)
>2
11
4
45 (20-57)
Not in MMR
<1
32
2
35 (10-70)
>1
8
4
25 (12-56)
Disclosures: Kantarjian: Bristol Myers Squibb: Research Funding; Novartis Pharmaceuticals: Research Funding;
MGI Pharma: Research Funding. O'Brien: Bristol Myers Squibb: Research Funding; Novartis Pharmaceuticals:
Research Funding. Jabbour: Novartis Pharaceuticals: Speakers Bureau; Bristol Myers Squibb: Speakers
Bureau. Cortes: Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Wyeth:
Research Funding.
2113 Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib
Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of
Response
Sunday, December 7, 2008
Hall A (Moscone Center)
Poster Board II-207
Susan Branford1, Rebecca Lawrence1*, Andrew Grigg2, John Francis Seymour, MBBS3, Anthony Schwarer4,
Christopher Arthur4, Zbigniew Rudzki1* and Timothy Hughes1
1Institute of Medical & Veterinary Science, Adelaide, Australia
2Med. Onc./Hem., Royal Melbourne Hospital, Melbourne, Australia
3Peter MacCallum Cancer Institute, Richmond, Australia
4Australasian Leukaemia & Lymphoma Group, Australia
A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with
newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast
crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined
whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL
mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since
commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored
regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct
sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3-96m). The event rate was
compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of
imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also
determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis
indicated BCR-ABL was <0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was
confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed >2 fold rise from nadir to a level
>0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3-53m).
Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with
a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of <600mg in
the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the
first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a
median of 9m (r 3-42m). An event occurred in 8 pts with MMR at a median of 36m (r12-57m) after commencing
imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The
remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold
rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with
mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of
MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of
follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4-220). The probability of an event if
MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) >6 to 12m was 12% (n=40) and c) 12 to 18m was
19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r
3-87m), 38m (r 6-87m), 40m (r 9-78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by
6m was significantly lower than in pts with MMR achieved by >6 to 18m, P=0.04. CMR occurred in 55 pts who
were followed for a median of 24m (r 3-55m) after its attainment. Only 1 event occurred in these 55 pts, which
was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for
45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference
in the probability of CMR by 60m of imatinib dependent on the time to MMR, P<0.0001 (Figure). All pts failed to
achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with
MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The
mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those
with MMR at >6 to 12m and >12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of
BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial
as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier
molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and
deeper responses. It remains possible however, that early molecular response reflects a more biologically
favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated
with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved.
1108 Determining the Rise in BCR-ABL RNA That Optimally Predicts a Kinase Domain Mutation in
Patients with CML on Imatinib
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-213
Richard D. Press, MD, PhD1, Stephanie G Willis2*, Jennifer Laudadio3*, Michael J. Mauro, MD4 and Michael W.
N. Deininger, MD5
1Prof. & Dir. of Molecular Pathology, Oregon Health & Science Univ., Portland, OR
2Center for Hematologic Malignancies, OHSU Cancer Institute, Portland, OR
3OHSU Pathology
4Oregon Health & Science University, Portland, OR
5Oregon Health & Science University Cancer Institute, Portland, OR
The most common mechanism of imatinib resistance in patients with CML is point mutations in the BCR-ABL
kinase domain (KD) that impair imatinib binding to its target. As the second-line BCR-ABL inhibitors nilotinib and
dasatinib show activity in most patients with KD mutations, early identification of mutations may prevent relapse.
Current consensus recommendations are to perform mutation analysis if patients fail to achieve certain
milestones of response, or experience loss of response. Since most patients are routinely monitored by BCR-
ABL quantitative polymerase chain reaction (RQ-PCR), it is necessary to determine the optimal increase in BCR-
ABL RNA that should trigger mutation testing, while minimizing both false-positive and false-negative test results.
Recognizing the lack of a consensus, expert panels and the NCCN guidelines have provisionally recommended
mutation screening in cases with a 10-fold or greater increase of BCR-ABL RNA. To address, in an unbiased
fashion, the optimal transcript level rise associated with a mutation, and thus advise when mutation screening
should be performed, 150 CML patients were serially monitored (median 46 months post-imatinib) by RQ-PCR
and KD DNA sequencing. Thirty-five different mutations were identified in 53 patients, at a median of 28 months
after imatinib initiation. During 22.5 months of follow-up after mutation screening, relapses occurred in 85% of
the patients with a mutation (median 10. 4 months later) versus 46% of those with no mutation (median 32.4
months later) (hazard ratio = 3.2; P<0.0001). An unbiased receiver operating characteristic analysis identified a
2.6-fold increase in BCR-ABL RNA as the optimal cutoff for predicting a concomitant KD mutation, with a
sensitivity of 77% for samples drawn at the same time as mutation discovery, and a sensitivity of 94% if including
subsequent samples. At this 2.6-fold threshold, the negative predictive value was 97%, implying a small 3% risk
of failing to detect a deleterious point mutation when the BCR-ABL RNA increase does not reach this optimized
cutoff level. The 2.6-fold threshold approximated the analytical precision limit of our PCR assay. The table
shows the diagnostic sensitivities, specificities, negative predictive values, and odds ratios for predicting a
concomitant KD mutation at various rising RQ-PCR cutoff thresholds, including the optimal cutoff value of a 2.6-
fold increase in BCR-ABL RNA. All cutoff values between a 2- and 4.5-fold increase were significantly predictive
of a concomitant mutation, with 2.6-fold being the optimal cutoff level by several criteria (Youden index, negative
predictive value, and odds ratio). In contrast, cutoff rises of 5- or 10-fold had poor diagnostic sensitivity (missing
those 53-74% of mutation cases with lower levels of transcript rises), and were not significantly predictive of
mutations. We conclude that a transcript level rise of >2.6-fold is the optimal cutoff to trigger reflex mutation
screening in imatinib-treated CML. Furthermore, the currently recommended 10-fold threshold to trigger
mutation screening may be overly stringent and is not universally applicable.
RQ-PCR Increase (fold change)
Sensitivity (95% CI) (%)
Specificity (%)
Negative Predictive Value (95% CI) (%)
Odds Ratio (95% CI)
P
2.0
77 (62-88)
44
88 (80-94)
2.6 (1.2-5.4)
0.01
2.5
77 (62-88)
46
89 (81-94)
2.8 (1.4-5.9)
0.005
2.6
77 (62-88)
47
89 (81-94)
2.9 (1.4-6.0)
0.005
2.6* (include subsequent sample)
94 (82-99)
47
97 (91-99)
13 (3.9-43)
<0.0001
3.0
74 (60-86)
48
88 (80-94)
2.7 (1.3-5.5)
0.008
3.5
64 (49-77)
54
86 (78-91)
2.1 (1.1-4.1)
0.03
4.0
60 (44-74)
60
85 (78-91)
2.2 (1.1-4.2)
0.02
4.5
55 (40-70)
64
85 (78-90)
2.2 (1.2-4.2)
0.02
5.0
47 (32-62)
68
84 (77-89)
1.9 (1.0-3.6)
0.06
10
26 (14-40)
83
82 (75-87)
1.7 (0.8-3.7)
0.2
*Except for the one indicated row, the table includes only those patients with successful RQ-PCR and
sequencing performed on the same sample. If samples after the initial genotype determination are included, at
the optimal 2.6-fold cutoff, the sensitivity, NPV, and OR each increase.