[25] IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly
Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. Session Type: Oral Session
Andreas Hochhaus, Brian J. Druker, Richard A. Larson, Stephen G. O'Brien, Insa Gathmann, Francois Guilhot Med. Fakultaet
Mannheim, University of Heidelberg, Mannheim, Germany; Oregon Health Sciences University, Portland, OR, USA; University
of Chicago, Chicago, IL, USA; University of New Castle, New Castle, United Kingdom; Novartis, Basel, Switzerland; CHU de
Poitiers, Poitiers, France
Background: The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has
superior safety and efficacy relative to interferon- plus cytarabine (IFN+ara-C). Patients on the imatinib arm achieved an
estimated 5-year OS of 89%. To monitor the long-term responses achieved by patients on imatinib, the 6-year follow-up of the
IRIS patient population is summarized. Methods: 1106 patients were randomly assigned to either imatinib or IFN+ara-C and
evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis
(BC), overall survival (OS), and frequency of adverse events and discontinuations. Results: The downward trend in the risk of
disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of
transformation to AP/BC attained between years 5 and 6. Of 553 who were randomized to imatinib, 364 (65.8%) remain on
study drug at 6 years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) pts have discontinued from imatinib study
therapy for any reason. The following reasons were cited for discontinuation from the IRIS study: adverse events, 23 patients
(4.2%); unsatisfactory therapeutic effect, 66 patients (11.9%); protocol violation, 15 patients (2.7%); withdrawal of consent,
32 patients (5.8%); administrative problems, 6 patients (1.1%); and 16 patients (2.9%) elected to undergo a stem cell
transplantation (SCT). Death was the reason for discontinuation for 10 (1.8%) patients, and 7 patients (1.3%) were lost to
follow-up. The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The
best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%,
respectively, with 2 additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are
still in CCyR, another 24 had lost CCyR but regained it, 6 patients lost CCyR but remain in MCyR, and the remaining 9 patients
never had a documented CCyR. Overall, an estimated 83% of patients were event-free, and 93% were free of progression to
AP or BC at 6 years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second
year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up,
a total of 66 (12%) patients have died (19 after SCT, 27 not due to CML). Estimated 6-year OS rate for all patients who
received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to
transplant, the estimated OS at 6 years is 91%. In an analysis of serious adverse events, no new safety issues were identified
between the 5-year report and this analysis. Conclusions: The 6-year follow-up analysis of the IRIS population indicates that
continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a
decreasing rate of relapse and a favorable long-term safety profile.
[1033] A Phase 3 Pilot Study of Continuous Imatinib Versus Pulsed Imatinib with or without G-CSF in Patients with
Chronic Phase CML Who Have Achieved a Complete Cytogenetic Response to Imatinib. Session Type: Poster
Session, Board #187-I
Nicholas Heaney, Mark Drummond, Jaspal Kaeda, Franck Nicolini, Richard Clark, George Wilson, Pat Shepherd, Jane Tighe,
Lorna McLintock, Timothy Hughes, Tessa L. Holyoake Experimental Haematology, Glasgow University, United Kingdom;
Haematology, Imperial College at Hammersmith Hospital, London, United Kingdom; Haematology, Hospital e Herriot, Lyon,
France; Haematology, University of Liverpool, United Kingdom; Haematology, Western General Hospital, Edinburgh, United
Kingdom; Haematology, Aberdeen Royal Infirmary, United Kingdom; Molecular Pathology, IMVS, Adelaide, Australia
Imatinib mesylate (IM) induces complete cytogenetic responses (CCR) in the majority of patients with CML in chronic phase
(CP). Despite this reduction in disease burden many patients continue to have detectable Bcr-Abl transcripts in peripheral blood.
We believe that IM-resistant Ph+ haemopoietic stem cells (HSC) contribute to this residual disease. IM has been shown to
selectively target proliferating CML HSC, while simultaneously exerting an antiproliferative effect on the quiescent
population-causing accumulation. We have previously characterised these quiescent cells and shown that intermittent in-vitro
exposure of Ph+HSC to exogenous G-CSF leads to a reduction in number of quiescent and total HSC in culture (Clin Can Res
2006, 12: 626). This randomised, multi-centre, pilot phase 3 study was established to determine the safety and efficacy of
combining G-CSF with IM in patients with CP CML who had achieved CCR on IM. 45 patients were equally randomised
between 3 arms: continuous IM (cIM); pulsed IM (pIM 3 weeks IM and 1 week no drug); and pIM-G-CSF (pIM-G 3 weeks
IM and 1 week G-CSF). The dose of IM administered was the dose on which the patient had achieved CCR. Patients had a
median age of 59y (25-76y) and had been diagnosed with CML for a median of 36m (8-171m). 21 patients had prior IFN
therapy with 4 autografted. Hasford scores were 36% low, 46% Intermediate, and 18% high. At baseline 25 patients had a
major molecular response (MMR cIM 7, pIM 8, pIM-G 10). Patients were assessed monthly for 1 year with clinical
examination, routine blood tests and Bcr-Abl Q-RT-PCR. Significant cardiovascular events were seen in 2 patients - 1 patient
died of myocardial infarction (pIM-G) and 1 survived a stroke (cIM). There was a trend to less IM-associated side effects
(diarrhoea, muscle cramps) in the experimental arms, though bony pain was reported in pIM-G (5 patients). Statistical analysis
(ANCOVA) was performed on Bcr-Abl readings taken during the trial and no significant difference was detectable between the
3 arms. Further end-point analyses showed that 4 achieved MMR (4 cIM) 21 maintained MMR (6 cIM, 6 pIM, 9 pIM-G) and 7
showed disease progression with loss of MMR (1 cIM, 2 pIM, 1 pIM-G) and/or loss of CCR (2 pIM, 1 pIM-G). 4 patients
were withdrawn as a result of disease progression (3 pIM, 1 pIM-G). In conclusion both experimental arms appeared safe and
well tolerated. In this pilot study there was no clear difference in efficacy when either pIM or pIM-G was compared to cIM,
despite the 25% effective dose reduction of IM in the experimental arms. The absence of a clear benefit means that this
approach cannot be recommended as an alternative to standard IM dosing, however may be applicable to a selected group of
patients who cannot tolerate standard daily dosing.
[1047] Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).
Session Type: Poster Session, Board #201-I
Hagop M. Kantarjian, Brian J. Druker, Francois Guilhot, Jorge Cortes, Stephen G. O'Brien, Tillmann Krahnke, Richard A.
Larson University of Texas MD Anderson Cancer Center, Houston, TX, USA; Oregon Health Sciences University, Portland,
OR, USA; CHU de Poitiers, Poitiers, France; University of New Castle, New Castle, United Kingdom; Novartis Pharma AG,
Basel, Switzerland; University of Chicago, Chicago, IL, USA
Background: Imatinib mesylate (IM) 400 mg/d is the standard of care for newly diagnosed patients (pts) with CML-CP. Dose
escalation to 600 or 800 mg IM has been shown to be beneficial in patients with either an inadequate response or disease
progression while on standard therapy (Kantarjian et al Blood 2003). In the International Randomized study of Interferon versus
STI571 (IRIS) trial, initiated in 2000, dose escalation was allowed for patients who did not achieve a complete hematologic
response (CHR) by 3 months or a minor cytogenetic response (minCyR) by 12 months, lost a major cytogenetic response
(MCyR) at any time, or progressed (including increase in WBC); no dose escalation in cases of loss of CCyR were specified.
The impact of IM dose escalation for patients on IRIS is presented in this post-hoc analysis. Methods: Patients were evaluated
for hematologic and cytogenetic responses, progression (to accelerated or blast phase) free survival (PFS), and overall survival
(OS) following dose escalation. Patients were included if their dose was increased within -0.5 to 3 months following the
respective landmark evaluation. Instances of dose escalation (to 600 mg/d) on the IM arm were reviewed and classified, where
possible, based on either criteria established by IRIS protocol or the European LeukemiaNet recommendations Results: Of 551
patients receiving first line IM, 106 pts (19%) had dose escalation to 600-800 mg/d. Median time to dose escalation was 22
months (range:3-74 months; 25th-75th percentile: 13-45 months). After dose escalation the median imatinib dose delivered was
604 mg/d (range: 294-800 mg/d; 25th-75th percentile:600-739 mg/d) and remained on treatment for a median of 19.4 months
based on current follow-up. Last recorded dose was 600mg/d in 85% of these patients. Dose increases in 39 patients were
based on the IRIS protocol criteria. Responses among these patients included: 6 of 7 who had not achieved CHR at 3 months
achieved a CHR with dose escalation, 2 of these patients subsequently achieved a CCyR. Of 8 patients who had not achieved a
minCyR at 12 months, 4 improved to a CCyR, and of 18 patients who lost their MCyR, 9 subsequently re-achieved an MCyR
within 12.5 months after dose escalation, of whom 3 also attained a CCyR by 30-months after dose escalation. The 6 patients
who received dose escalations upon progression, had an OS of 83% at 2 years after dose escalation. At 36-months after dose
escalation the 39 patients dose escalated per IRIS protocol criteria achieved an estimated PFS and OS of 81%. In a separate
analysis of these 106 pts, dose escalations in 48 pts were retrospectively classified according to the ELN recommendations. At
36-months follow-up after dose escalation these 48 patients achieved a 90% PFS and 89% OS. For the entire cohort of 106
patients who were dose escalated, estimated PFS was 89% and OS was 84% at 36 months after dose escalation. Conclusion:
Based on these data, IM dose escalation to 600 and/or 800 mg allows poorly responding patients to achieve a clinically
important durable response or re-gain responses. These slower responding or progressing patients benefited from IM dose
escalation and thus, the data support dose escalation for these patients.
[1043] Imatinib Dose Can Be Safely Reduced after Complete Cytogenetic Response (CCyR) in Patients (pts) with
Chronic Myeloid Leukemia (CML) in Early Chronic Phase (CP) Treated with High-Dose Imatinib. Session Type:
Poster Session, Board #197-I
Nitin Jain, Hagop M. Kantarjian, Carmen Fava, Deborah Thomas, Jan A. Burger, Gautam Borthakur, Odeal Pate, Jorge Cortes
Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
Background Imatinib (standard dose, SD, 400mg/d) is standard therapy in CP CML. Several observations suggest that initial
therapy with high-dose (HD) imatinib might be more effective. We previously reported that HD imatinib (800mg/d) leads to
significantly better rates of complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular
response (CMR), and improved event-free survival compared to SD. However, HD imatinib is associated with more frequent
grade 3-4 hematological toxicity compared to SD. In addition, 36% pts required dose reduction due to toxicities. We
investigated the outcome of pts who were maintained on 800mg/d compared to those whose dose was reduced from 800mg/d.
Methods Pts enrolled in 3 sequential trials using imatinib for frontline therapy for CP CML were analyzed: 208 treated with HD
and 50 with SD. Primary end points were event-free survival (EFS) and transformation-free survival (TFS). Results The
median age was 48 years (range 17-84 years). Median follow up was 49 months. 4 year event-free survival (EFS) and
transformation-free survival (TFS) were significantly better for pts treated with HD imatinib compared to SD (EFS: 92% vs.
77%, p=0.01; TFS: 98% vs. 89%, p=0.0045). Among pts treated with HD, 100 (48%) had a dose reduction at any time
[600mg/d (n=50), 400mg/d (n=38), 300mg/d (n=12)]. Of them, 45 (45%) were dose-reduced after achieving CCyR including
26 (26%) after MMR. The median time to dose reduction was 3 months (range 1-60 months). For pts starting with HD
imatinib, there was no difference between pts continuing with HD and those with a dose reduction in terms of EFS at 4 years
(92% in both groups, p=0.65) and TFS at 4 years (98% vs. 97%, respectively, p=0.36). However, EFS at 4 years was
significantly worse if the dose reduction was done prior to achievement of CCyR (84% vs. 100%, p=0.02). Similarly, patients
who were dose-reduced before MMR had significantly worse 4 year EFS (88% vs. 100%, p=0.02). EFS curve for patients
who had dose reduction done prior to CCyR was similar to that of pts treated with SD imatinib (p=0.59). Conclusions These
results indicate that pts treated with HD imatinib can be safely dose reduced once they have achieved CCyR (preferably MMR)
without having any impact on EFS or TFS. Such dose reduction may help decrease side effects as well as cost of the
treatment. A prospective evaluation of this approach is warranted.
[1956] Kinetics of Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients May Predict Persistent
Polymerase Chain Reaction Negativity after Imatinib Discontinuation. Session Type: Poster Session, Board #146-II
Giovanna Rege-Cambrin, Stefano Ulisciani, Giovanna Mattioli, Carmen Fava, Emilia Giugliano, Vanessa Brunetto, Enrico
Gottardi, Milena Fava, Giuseppe Saglio Internal Medicine, University of Turin, S.Luigi Hospital, Orbassano, Italy
Achieving a molecular response after imatinib treatment is considered today the gold standard on Ph+ CML therapy. However,
only a restrict group of patients is able to achieve a complete molecular response (CMR). Based on a mathematic model, it has
been suggested that imatinb reduces the rate at which differentiated cells are produced from leukaemic stem cells, with no
significant effect in reduction of Ph+ stem cells (Michor F et al, Nature 2005). So, cure of the disease is still considered to be
restricted to allogeneic bone marrow transplant. Clinical data obtained in patients who stop treatment can be of great value in
evaluating the degree of suppression of the neoplastic clone. We report 6 cases of patients with CML in complete cytogenetic
remission (CCyR) who interrupted imatinib treatment. Stop was due in 5 cases to some degree of toxicity whereas one male
patient decided to stop for personal reasons. All patients were in chronic phase and previously achieved a CCyR within 12
months after imatinib start; major molecular remission (MMR) was observed in 5 cases, and 4 of them also showed a CMR in
at least one occasion.After discontinuation, three patients had a molecular or cytogenetic relapse in a period of 3 to 6 months.
In these cases, CMR was never reached, or in one case it was delayed in time, being observed after 3 years of treatment, and
not confirmed in all subsequent samples. All patients responded again to imatinib treatment. Three other patients did not relapse
and are PCR-negative with a follow-up of 18, 22 and 39 months respectively. One of them received imatinib for cytogenetic
relapse after IFN + ARA-C, whereas two patients were treated with Peg-IFN and imatinib front-line; Peg-IFN was stopped for
toxicity in both cases. At imatinib stop, they all were in sustained complete molecular remission, as defined by undetectable
BCR-ABL transcript at RT- and RQ-PCR both on BM and PB samples, in multiple serial samples. In these three patients, CCyR
was reached whithin 3 months of imatinib therapy and CMR was achieved after 1 year, 6 months, and 9 months respectively,
and never lost. The median duration of treatment before discontinuation was 45,5 months, while the median time of PCR
negativity on imatinib was 39 months. In most reported cases, imatinib discontinuation results in relapse after few months
(Cortes J et al, Blood 2004; Michor F et al, Nature 2005; Mauro MJ et al, Leuk Res 2004). However, both time of treatment
and duration of molecular response were relatively short in these reports. Recently, 12 patients who stopped treatment when in
CMR for more than two years have been published (Rousselot P et al, Blood 2007): 6 of them relapsed early whereas 6 remain
in CMR after a median follow-up of 18 months. We describe 3 cases who are persistently PCR-negative after imatinib
discontinuation, with a median follow-up of 26 months; all of them were characterized by a rapid clearance of leukemic cells
after start of imatinib, which allowed to obtain a stable CMR within the first 12 months of treatment. Less than 5% of early CP
patients on imatinib achieve CMR in the first year (Brandford S et al, Blood 2006). These data suggest that kinetics of molecular
response achievement may predict prolonged response after imatinib discontinuation, possibly reflecting a decline in leukemic
stem cell compartement.
[28] Sustained Molecular Responses with Interferon 2a Maintenance Therapy after Imatinib Plus IFN Induction
Treatment for Chronic Phase Chronic Myelogenous Leukemia. Session Type: Oral Session
Andreas Hochhaus, Andreas Neubauer, Martin C. Mueller, Simone Napieralski, Philipp Erben, Tilman Bostel, Ruediger
Hehlmann, Andreas Burchert 3. Med. Klinik, Medizinische Fakultaet Mannheim, Universitaet Heidelberg, Mannheim, Germany;
Klinik f. Innere Medizin, Haematologie, Onkologie und Immunologie, Universitaetsklinikum Giessen und Marburg, Marburg,
Germany
Most patients with chronic myelogenous leukemia (CML) relapse after discontinuation of imatinib (IM, Glivec/Gleevec). Thus,
current recommendations suggest a lifelong IM therapy even in complete molecular responders. However, in view of potential
long term adverse effects there is a concern of tyrosine kinase inhibition. Hence, strategies to circumvent permanent kinase
inhibitor therapy would be of substantial clinical value. Interferon (IFN), in contrast to IM, elicits an autologous antileukemic
immune response to control CML, and stopping IFN in complete cytogenetic responders is not associated with relapse in a
significant proportion of patients. We therefore sought to determine efficacy and tolerability of an IFN maintenance
immunotherapy after IM/IFN induction in newly diagnosed chronic phase CML patients. Twenty patients (14 m, 6 f; median
age 44.6, range 23.5-74.1 years) have been investigated. Hasford score revealed low (n=13), intermediate (n=6), and high risk
(n=1) diseases. IM therapy had been administered for 2.4 yrs (0.2-4.9), combined with PEG-IFN2a (Pegasys, n=17) or IFN2a
(Roferon, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response
and tolerability and ranged between 135 g PEG-IFN every three weeks to 180 g PEG-IFN once weekly week, or alternatively
between 2 to 5*3 Mill IU IFN/week. IM was stopped due to side effects (n=5) or after the patients individual request and
informed consent (n=15). At the time of imatinib withdrawal, 19 patients were in complete cytogenetic remission and one
patient did not show any cytogenetic response. Major molecular response was determined in peripheral blood leukocytes of 16
patients, including one patient with undetectable BCR-ABL transcripts. After a median observation time of 1.2 yrs (range
0.1-3.1), 15 patients showed major molecular response, seven of them were complete. Improvement of molecular response
was observed in seven and a stable situation in ten patients. By 6 weekly assessments of BCR-ABL expression gradual
molecular relapse was observed in three patients. All relapsing patients responded to readministration of IM. At the time of IM
withdrawal and during IFN maintenance therapy myeloblastin (proteinase-3, PR3) mRNA expression was determined and
compared to glucose-6-phosphate dehydrogenase transcripts as internal standard. During IFN monotherapy, median ratios
PR3/G6PD increased from 0.06% (range, 0.02-3.5) to 0.14% (0.03-1.4; p=0.03). IFN response was associated with the
detection of autoreactive PR3 specific T-lymphocytes during IFN maintenance therapy determined by a tetramer assay in 7/8
patients, suggesting that PR3-specific cytotoxic T lymphocytes contribute to the IFN-mediated antileukemic immunity. In
conclusion, we report a high rate of improved or continuous molecular remissions in 17 of 20 patients (85%) on IFN
monotherapy after prior induction with IM/IFN. This suggests a previously unrecognized beneficial role for IFN in the
maintenance therapy after IM-mediated debulking and may impact future CML therapy.