1126 International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year
Follow up: Sustained Survival and Low Risk for Progression or Events in
Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase
(CML-CP) Treated with Imatinib
Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy Poster I
Saturday, December 5, 2009, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board I-148
Michael Deininger, MD, PhD1, Stephen G O'Brien, MD, PhD2*, François Guilhot, MD3, John M Goldman, DM,
FCRP4*, Andreas Hochhaus, MD5*, Timothy P. Hughes, MD, MBBS6, Jerald P. Radich, MD7*, Alan K. Hatfield,
MD, FACP8, Manisha Mone, PhD8*, Jeiry Filian8*, John Reynolds9*, Insa Gathmann9*, Richard A. Larson,
MD10 and Brian J. Druker, MD11
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR
2Newcastle University Medical School, Newcastle, United Kingdom
3Oncology, Hematology, and Cell Therapy, Clinical Investigation Centre CIC P 802 INSERM, Poitiers, France
4Imperial College School of Medicine, London, United Kingdom
5Abt. Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
6Department of Haematology, SA Pathology, Royal Adelaide Hospital, Adelaide, Australia
7Fred Hutchinson Cancer Research Center, Seattle, WA
8Novartis Pharmaceuticals Corporation, East Hanover, NJ
9Novartis Pharma AG, Basel, Switzerland
10University of Chicago, Chicago, IL
11Oregon Health & Science University Knight Cancer Institute, Portland, OR
Background: The IRIS study demonstrated superior safety and efficacy of imatinib (IM) relative to interferon-α +
cytarabine. Based on results from this trial, IM is currently recommended as front-line therapy for CML-CP
patients (pts). We report 8-yr follow-up of IRIS, evaluating long-term efficacy and safety of IM. Methods: The
553 pts randomized to first-line IM were evaluated for cytogenetic and molecular responses, event-free survival
(EFS), progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), discontinuations, and
frequency of serious adverse events (SAEs). EFS was defined as time until the first occurrence of any of the
following: death from any cause, progression to AP/BC, loss of a complete hematologic response or major
cytogenetic response, or an increasing white cell count to > 20 x 109/L. Yearly progression rates were
calculated using the life-table method considering available follow-up. Following study drug discontinuation, pts
were followed for OS and stem cell transplant (SCT) information. Results: At the 8-yr data cut-off, 304 (55%) pts
remained on IM study treatment, and 45% had discontinued treatment due to adverse events (AEs)/safety
(6%), unsatisfactory therapeutic outcome (16%), SCT (3%), death (3%) or other reasons (17% for withdrawal or
lack of renewal of consent and miscellaneous). No new safety issues were identified in a long-term analysis of
serious adverse events.
Estimated EFS at 8 yr was 81% and freedom from progression to AP/BC was 92%. Estimated OS was 85% at 8
yr, and 93% when only CML-related deaths and those prior to SCT were considered. Three events occurred in
yr 8: 1 progression to AP/BC and 2 deaths unrelated to CML (chronic obstructive pulmonary disease [1];
pneumonia aspiration [1]). The annual rates of progression to AP/BC in yr 4 to 8 after initiation of therapy were
0.9%, 0.5%, 0%, 0%, & 0.4%, respectively. Only 15 (3%) pts who achieved complete cytogenetic response
(CCyR) progressed to AP/BC, all but 1 within 2 yr of achieving CCyR.
BCR-ABL transcript numbers were monitored sequentially in 98 pts. Among these, the rate of major molecular
response (MMR, < 0.1% BCR-ABL/control gene ratio on international scale) increased from 24% at 6 months
(mo) and 39% at 12 mo to a best observed MMR rate of 86% with current follow-up. None of the pts with
documented MMR at 12 mo progressed to AP/BC.
To establish the relationship between early cytogenetic response (CyR) status and subsequent outcomes
during 8 yr of IM treatment, we compared the cumulative incidence of achieving stable CCyR (defined as CCyR
without subsequent event) vs the probability of an event (as described above but excluding CML-unrelated
deaths) according to levels of CyR at 3, 6, 12, & 18 mo (Table 1). Pts with minor to partial CyR (> 0–65% Ph+
metaphases) at 3 mo and those with partial CyR (PCyR; > 0–35% Ph+ metaphases) at 6 & 12 mo were more
likely to achieve a stable CCyR than have an event. Among pts with less than CCyR at 18 mo, the probability of
an event was comparable to the probability of achieving stable CCyR.
Table 1. Cumulative incidence of CCyR vs estimated event rate 8 yr after starting IM
[with 95% confidence interval]
Time on therapy at karyotyping
Cytogenetic Response
(% Ph+) 3 mo 6 mo 12 mo 18 mo
Stable CCyR % Est. event rate % Stable CCyR % Est. event rate % Stable
CCyR % Est. event rate % Stable CCyR % Est. event rate %
0
(CCyR) - 6
[1,11] - 7
[3,11] - 6
[2,9] - 3
[1, 6]
>0–35
(PCyR) 72
[65,80] 10
[5,15] 63
[53,73] 17
[8,26] 57
[42,72] 20
[7,33] 29*
[16,42] 31*
[15,46]
>35–65
(minor) 55
[39,71] 30
[15,45] 35
[15,55] 38
[16,60] 14*
[2,25] 62*
[42,81]
>65–95
(minimal) 37
[19,54] 32
[13,51] 25
[3,47] 45
[20,71]
>95
(None) 32
[16,47] 40
[22,58] 32*
[10,53] 36*
[12,60]
*Cytogenetic response is considered “failure” according to European LeukemiaNet (ELN) guidelines.
Conclusions: CML-CP pts responding to IM had a low overall risk of progression to AP/BC. Most AP/BC events
occurred early, with minimal risk after yr 3 and no evidence for an increase over time. Minor CyR at 3, PCyR at
6 and 12, and CCyR at 18 mo were associated with stable CCyR over the observation period. The safety profile
of IM remains unchanged after 8 yr, with no previously unreported AEs identified over the past 36 mo. These
data suggest that pts responding to IM are likely to maintain their responses on long-term therapy and confirm
a favorable risk-benefit ratio in CML-CP pts.
643 A Phase 1 Trial of Oral AP24534 in Patients with Refractory Chronic Myeloid
Leukemia and Other Hematologic Malignancies: First Results of Safety and
Clinical Activity against T315I and Resistant Mutations
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: Managing Resistance and Residual Disease
Monday, December 7, 2009: 4:30 PM
Conference Auditorium AB (Ernest N. Morial Convention Center)
Jorge Cortes, MD1*, Moshe Talpaz, MD2, Michael Deininger, MD, PhD3, Neil Shah, MD, PhD4, Ian W Flinn,
MD5, Michael J. Mauro, MD3, Thomas O'Hare, PhD6*, Natalie Spinos7*, Simin Hu, PhD7*, Lori Berk7*,
Narayana Narasimhan, PhD7*, Victor M. Rivera, PhD7, Tim Clackson, PhD7*, Frank Haluska, MD, PhD7* and
Hagop M. Kantarjian, MD1
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Comprehensive Cancer Ctr., University of Michigan, Ann Arbor, MI
3Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR
4University of California, San Francisco, San Francisco, CA
5Sarah Cannon Research Institute, TN
6Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR
7ARIAD Pharmaceuticals, Inc., Cambridge, MA
AP24534 is an orally available multiple tyrosine kinase inhibitor (TKI) designed using a structure-based
approach as a pan-BCR-ABL inhibitor. AP24534 potently inhibits the enzymatic activity of BCR-ABL-T315I, the
native enzyme and all other tested variants. It also inhibits survival of cell lines expressing these BCR-ABL
variants with IC50s of < 40 nM, and inhibits Flt3 and c-Src. We report here preliminary results from our ongoing
phase 1 clinical trial. The objectives of this study are to assess the safety of AP24534, establish a maximum
tolerated dose and schedule for further investigation, and provide preliminary assessments of clinical activity.
The trial employs an open-label dose escalation design. Patients (pts) with hematologic malignancies
refractory to treatment, ECOG status ≤ 2, adequate hepatic and renal function, and normal cardiac function are
eligible and receive a single daily oral dose of AP24534. Thirty-two pts (16 males) have been enrolled, median
age 63 years (range 31-79). Diagnoses include 27 CML (19 chronic [CP], 4 accelerated [AP], 4 blast phase
[BP]), 1 Ph+ ALL, 2 myelofibrosis, 1 myeloma, 1 MDS. BCR-ABL mutation status in 28 Ph+ pts included 5 pts
with no mutation, 12 T315I (8 at entry, 4 by history), 3 F317L, (2 at entry, 1 by history), 2 M351T, and 1 each
L273M/F359V, G250E, E279K, F359C, L387F and E453K. Prior therapies in CML pts included imatinib (100%
of pts), dasatinib (94%), nilotinib (53%), interferon (47%), chemotherapy (41%), and investigational (65%); 83%
were resistant to 3 or more TKIs. Pts have been treated at the following dose levels: 2 mg (3 pts), 4 mg (6 pts),
8 mg (7 pts), 15 mg (8 pts), 30 mg (7 pts), and 60 mg (1 pt). 21 pts remain on study. Of 23 pts in the 4 highest
(8-60 mg) dosing cohorts, 19 remain on study. Median time on study drug is currently 3.4 months (range 5 days
to 10 months). At the time of this report, preliminary safety and efficacy data are available for 31 patients. No
DLTs have been observed. The most common drug-related adverse events (AE) were nausea (15%), fatigue
and dry eye (12% each), anorexia, arthralgia, dizziness, dry mouth, headache, hot flush, myalgia, vomiting (8%
each), and QTc prolongation (1 pt in 2 mg, 1 pt in 4 mg cohort). Grade 3 or 4 thrombocytopenia occurred in
36% pts (18% entered with thrombocytopenia), and grade 3 or 4 neutropenia in 41% (18% entered with
neutropenia). Both types of hematologic toxicity were more frequent in pts with advanced stages of CML or
baseline cytopenia. Pharmacokinetic data demonstrate that the half life of the drug is 19-45 hours. The
relationship of Cmax to dose is linear over the dosing range. The Cmax on day 1 at the 30 mg dose is
approximately 55 nM. After one 28-day cycle, the AUC is 2.5- to 3-fold higher than single dose AUC. PD data
demonstrate inhibition of CrkL phosphorylation at doses of 8 mg and higher. Overall best hematologic
response was complete hematologic response (CHR) in 16 of 18 CP pts (88%), 5 of whom had CHR on entry,
major hematologic response (MHR) in 2 of 4 AP pts, and no response in 4 BP and 1 ALL pts. Cytogenetic
responses were 4 complete cytogenetic responses (CCyR) and 2 PCyR. Of the 12 patients with T315I
mutations, 9 remain on study without progression. Best hematologic response in the T315I subset was CHR in
5 of 6 CP pts (83%), 2 of whom had CHR on entry, MHR in 2 of 2 AP pts, resolution of extramedullary symptoms
in 1 BP pt, and no response in 2 BP and 1 ALL pts. Nine of 12 T315I pts are evaluable for CyR: 2 (1 CP, 1 AP)
achieved CCyR after 2 and 5 months (at 4 mg and 15 mg), and 1 CP achieved PCyR after 3 months at 15 mg.
Of 3 pts with dasatinib resistant F317L, 1 discontinued for an unrelated AE (CNS ischemia), and 2 remain on
study in CP at 8 and 15 mg. One pt with nilotinib resistant F359C remains on study with CHR, CCyR, and major
molecular response after 4 months at 15 mg. Conclusions: No DLTs have been observed at doses up to 30 mg
AP24534. PK and PD demonstrate that blood levels at 30 mg exceed those needed for in vitro inhibition of
resistant mutant BCR-ABL isoforms, including T315I. Preliminary analysis reveals evidence of clinical antitumor
activity in patients with resistance to approved second-line TKIs dasatinib and nilotinib, including pts with the
T315I mutation of BCR-ABL.
859 Discontinuation of Imatinib Therapy After Achieving a Molecular Response
in Chronic Myeloid Leukemia Patients
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: New Trends in Management
Tuesday, December 8, 2009: 7:30 AM
293-296 (Ernest N. Morial Convention Center)
Francois-Xavier Mahon1*, Delphine Rea, MD, PhD2*, Francois Guilhot, MD3, Francoise Huguet4*, Franck
Emmanuel Nicolini, MD, PhD5, Laurence Legros6*, Aude Charbonnier7*, Agnes Guerci8*, Bruno R. Varet, MD9,
Gabriel Etienne, MD10*, Emilie Aton11*, Josy Reiffers, MD12* and Philippe Rousselot, MD, PhD13*
1Hématopoïése leucémique, Université Victor Segalen, Bordeaux, France
2Hopital Saint Louis, Paris, France
3Hopital Jean Bernard, Poitiers, France
4Dept. Hematology, Hopital de Purpan, Toulouse, France
5Hematology, Hopital Edouard Herriot, Lyon, France
6CHU de Nice, Nice, France
7Institut Paoli Calmette, Marseille, France
8CHU Brabois, Nancy, France
9Hematology Dept., Paris Descartes Univ. Necker Hospital, Paris, France
10Service d'Hematologie, Institut Bergonie, Bordeaux, France
11Hopital Haut Leveque - Pessac, Bordeaux, France
12Universite Victor Segalen Bordeaux 2, ARMA, Bordeaux, Cedex, France
13Hôpital André Mignot, Versailles, France
Background
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 multicentre study « Stop Imatinib » (STIM) was initiated in July 2007 in order to evaluate the
persistence of complete molecular remission (CMR) after stopping IM, and to determine the factors that could
be associated with CMR persistence.
Methods
Inclusion criteria were IM treatment duration of 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-challenged with
IM at 400 mg daily.
Results
From the pilot study, 8 among 15 patients are still in CMR with a median follow up of 42 months (range 37-49).
The number of patients enrolled in the STIM study was 69. 34 patients had received interferon alpha (IFNa)
prior to IM and 35 pts were de novo. Median follow-up (range) was 17 months (6-24). 37 pts relapsed (loss of
CMR) within the first 6 months and two patient relapsed after more than 6 months (M7 ,M18). At M12, the
probability of remaining in CMR was 45% (95% CI: 33-56%). For previously treated with IFN (n=34) this
probability was 44% (95% CI: 27-59%) versus 46% (95% CI: 29-61%) for de novo pts (p=0.93, overall). All
patients in molecular relapse were sensitive again after imatinib re-challenge (decreasing BCR-ABL level,
achievement CMR again). Male pts had a better probability of survival without molecular relapse (p=0.02) and a
trend was observed for the low Sokal risk group (p = 0.06). Peripheral NK cells counts prior to IM
discontinuation were significantly lower in relapse pts (mainly cytotoxic cells CD56dim) as compared to the non
relapse pts(p=0.005).
Conclusions
We have confirmed that CMR can be sustained after discontinuation of imatinib with a long follow-up,
particularly in male patients and in pts with cytotoxic NK cells in their peripheral blood. Using stringent criteria, it
is possible to stop treatment in patients with sustained CMR, even in those treated with IM as a single agent.
647 Interferon Alpha 2a (IFN) Maintenance Therapy After Imatinib Plus IFN
Induction Therapy in Chronic Myeloid Leukemia (CML) Induces Stable Long-
Term Molecular Remissions and Is Associated with Increased Proteinase 3
(PR3) Expression and the Presence of PR1-Specific T-Cells
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: Managing Resistance and Residual Disease
Monday, December 7, 2009: 5:30 PM
Conference Auditorium AB (Ernest N. Morial Convention Center)
Andreas Burchert, MD1, Martin C Müller, MD2*, Philippe Kostrewa, cand., med.1*, Philipp Erben, MD2*, Tilman
Bostel, MD2*, Simone Liebler, MD1*, Rüdiger Hehlmann, MD2, Andreas Neubauer, MD3 and Andreas
Hochhaus, MD4
1Department of Hematology, Oncology and Immunology, Universitätsklinikum Giessen und Marburg, Marburg,
Germany
2Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
3Dept. Hematology, Oncology, Immunology, Philipps University Marburg, Marburg, Germany
4Department of Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany
Imatinib is a selective and very potent inhibitor of the BCR/ABL kinase. It induces ongoing complete cytogenetic
remissions in the vast majority of chronic phase CML patients. However, BCR/ABL persistence is the rule
despite ongoing imatinib therapy. This suggests that imatinib will not to cure CML and raises concerns about
emerging imatinib resistance, long-term imatinib tolerability and compliance to therapy. We previously
suggested that a combination of imatinib and immunotherapy by IFN may additionally control CML via induction
of autologous cytotoxic T-cell (CTL) responses, such as those directed against the leukemia-associated
antigen proteinase 3 (PR3). For example, induction of PR1-CTL which recognize PR3 on CML blasts was
previously shown to be associated with IFN-, but not imatinib response. Indeed, we could recently demonstrate
on a cohort of 20 newly diagnosed CML patients that low dose of IFN maintenance therapy alone was able to
maintain or improve remissions obtained by a prior imatinib/IFN combination treatment (A. Hochhaus et al. , ASH
2007). After a median time of IFN maintenance therapy of 1.2 years 80% of the patients remained or improved
molecular remission. Here we report a significantly longer follow up of these patients and translational studies to
examine markers of IFN response. Twenty pts (14 m, 6 f; median age 45, range 23-74 yrs) with low (n=13),
intermediate (n=6), and high risk (n=1) according to the Hasford score risk calculation have been investigated.
Imatinib therapy had been administered for 2.4 yrs (0.2-4.9), combined with PEG-IFNa2a (Pegasys®, n=17) or
IFN a2a (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 µg PEG-IFN every 3 weeks to 180 µg PEG-IFN
every week, or alternatively 2 to 5 * 3 Mill IU IFN/week. Imatinib was terminated due to side effects (n=5) or upon
personal request of the patients after informed consent (n=15). At the time of imatinib withdrawal, two pts were
in complete molecular remission (CMR) and 15 pts in major molecular remission (MMR). After a median
observation time of 2.8 yrs (range 0.5-4.5), 15 pts were in MMR, 5 of them in CMR. Thus, the number of MMR
patients increased from 2 at baseline to 5 after two years. Five patients relapsed within 0.4 years (range, 0.2-
0.8) after imatinib discontinuation, but were rescued with imatinib, re-establishing molecular remission. Side
effects to maintenance IFN were minor. We also studied putative markers of IFN response. IFN therapy was
associated with an increase in the expression of PR3, and in the presence of auto-reactive PR1-CTL. PR1-CTL
frequencies were prospectively assessed without prior in vitro amplification. In one of five assessable patients
PR1-CTL were detected prior to imatinib withdrawal, but in four of seven assessable patients during IFN
maintenance therapy. Longitudinal measurements of PR-1 CTL counts suggested an inhibition of the expansion
of PR1-CTL by imatinib, implying that an optimal CTL expansion may occur preferentially in the absence of
imatinib. This would explain the conversion to a CMR status in some patients only after imatinib withdrawal.
Together, IFN maintenance after a prior imatinib/IFN induction therapy may be an effective alternative to
permanent imatinib therapy, because it enables to safely discontinue imatinib even in those patients that have
not achieved a CMR at the time of pausing imatinib. Induction of a PR1-specific CTL response by IFN may
contribute to the particular efficacy of IFN after CML-debulking by imatinib.
505 Sustained Complete Molecular Response to Imatinib in Chronic Myeloid
Leukemia (CML): a Target Worth Aiming and Achieving?
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: Prognostic Factors
Monday, December 7, 2009: 2:45 PM
Conference Auditorium AB (Ernest N. Morial Convention Center)
Dushyant Verma, MD, FACP, Hagop M Kantarjian, MD, Jenny Shan, PhD*, Susan O'Brien, MD*, Amit Verma,
MD*, Elias Jabbour, MD, Srdan Verstovsek, MD, PhD, Tapan Kadia, MD, Mary Beth Rios, RN and Jorge Cortes,
MD
Leukemia, MD Anderson Cancer Ctr, Houston, TX
Background: Therapy with imatinib and other tyrosine kinase inhibitors leads to complete cytogenetic response
(CCyR) in 80-90% of patients in chronic phase (CP) of CML, but most patients have residual disease
documented by real-time quantitative polymerase chain reaction (PCR). Only a minority of patients achieve
complete molecular response (CMR), as defined by undetectable levels of BCR-ABL fusion transcripts by PCR
with sensitivity of at least 4.5 logs. Achieving CMR may offer the possibility of treatment discontinuation.
Aims: To identify patients with sustained CMR (CMR of at least 6 months consecutively on 2 different dates) so
as to define i) incidence of sustained CMR, ii) significance in long-term outcome (event-free survival, survival,
transformation), and iii) predictive factors for CMR.
Methods: We analyzed records of all patients with CML in early chronic phase (ie, within 12 months from
diagnosis) treated with imatinib as frontline therapy at MD Anderson Cancer Center from July 2000 to Aug
2009. Major molecular response was defined as a BCR-ABL/ABL ratio of ≤0.05%, and CMR as undetectable
transcripts in an assay with a sensitivity of at least 4.5 logs. Molecular responses were considered sustained
only if they met the criteria for response in at least 2 consecutive assays separated over a period of at least 6
months. All patients were followed by PCR every 3 months for the first 1-2 years, then every 3-6 months. Rates
of molecular response are reported on an intention-to-treat analysis.
Results: 281 patients were included: 271 in CP and 10 in CP with clonal evolution at the time of diagnosis. The
median age was 48 years (range 15-83), 119 (42%) were females, median CML duration 1 month (mo) (range
0-12). Seventy-three (26%) patients received an initial imatinib dose of 400 mg and 208 (74%) with 800 mg.
The median follow-up is 65 mo (range 2-107) with 249 (89%) treated for over 12 mo, 225 (80%) for over 24 mo,
211 (75%) for over 36 mo, 154 (55%) for over 60 months, and 29 (10%) treated for over 96 mo. 55 (20%) have
discontinued therapy (34 -12%-, because of resistance, and 21 -7%- because of intolerance). Overall, 248
(88%) achieved a CCyR, 80 (28%) a MMR without CMR, and 123 (44%) a CMR in at least one measurement.
MMR was sustained in 95 (34%) and CMR in 84 (30%). The median time to CCyR was 3 mo (range 2-30), to
sustained MMR 18 mo (range 6-78), and to sustained CMR 30 mo (range 6-84). The median event free survival
was not reached for patients in CCyR with CMR/MMR without CMR/no MMR. Among patients who did achieve a
CCyR, those that had a sustained CMR by 24 mo of therapy had an EFS of 100% at 5 yrs, compared to 96%
for those with MMR but no CMR, and 86% for those with CCyR but no MMR (p=0.02). The rate of survival free
from transformation to accelerated or blast phase at 5 yrs was 100% for those with CMR at 24 mo, compared to
96% for those with MMR but no CMR, and 91% for those with CCyR but no MMR (p=0.1). On univariate
analysis, factors predicting sustained CMR were platelet count >450x109/L (p=0.001), CCyR at 3 mo (p=0.
0005) and at 6 mo (p<0.0001).
Conclusion: These results suggest that achieving a CMR is an important endpoint for patients with CML treated
with imatinib as initial therapy. Treatment strategies that may increase the rate of sustained CMR should be
investigated.
509 Predictive Factors for Response and Outcome in Patients (pts) Treated with
Second Generation Tyrosine Kinase Inhibitors (2-TKI) for Chronic Myeloid
Leukemia in Chronic Phase (CML-CP) Post Imatinib Failure
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: Prognostic Factors
Monday, December 7, 2009: 3:45 PM
Conference Auditorium AB (Ernest N. Morial Convention Center)
Elias Jabbour, MD1, Hagop Kantarjian, MD1, Susan O'Brien, MD1, Jenny Shan, PhD1*, Guillermo Garcia-
Manero, MD2, William Wierda, MD, PhD1*, Farhad Ravandi, MD1, Gautam Borthakur, MD1, Mary Beth Rios,
RN1 and Jorge Cortes, MD1
1Leukemia Department, MD Anderson Cancer Center, Houston, TX
2Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
The availability of 2-TKIs has provided new therapeutic options for pts with CML post imatinib failure. We
assessed the predictive factors of outcome of pts in CML-CP treated with 2-TKI. A total of 128 pts with CML-CP
after imatinib failure treated with dasatinib (n=76) or nilotinib (n=52) were analyzed. Median age was 56 years
(range, 21-83). The median duration of CP (CML diagnosis to start of 2-TKI) was 66 months (range, 2-241).
Their best response to imatinib was complete hematologic response only in 33%, and cytogenetic response in
55% (23% complete, 16% partial, 15% minor). 4 pts were refractory to imatinib, 3 had unknown response, and 8
were intolerant. At the start of 2-TKI, 94 (73%) pts had active disease. 23% had clonal evolution (CE), and 73%
had more than 90% Philadelphia positivity. The median follow-up time was 39 months (range, 15-61) from the
start of the 2-TKI. At the time of last follow-up, 108 of the 128 pts (85%) were alive, 86 (67%) in CP on 2-TKI
therapy; 17 pts had died. Responses to 2-TKI are shown in Table 1. In the univariate analysis (UA) for event-
free survival (EFS), factors associated with poor EFS were splenomegaly, anemia (hemoglobin ≤12g/dL), lack
of any cytogenetic response to previous imatinib therapy, ≥ 90% Philadelphia-positive (Ph+) metaphases at the
start of 2-TKI therapy, nilotinib therapy, and high sokal risk score disease. In the subsequent multivariate
analysis (MVA), splenomegaly, anemia (hemoglobin ≤12g/dL), lack of any cytogenetic response to previous
imatinib therapy, and ≥ 90% Ph+ metaphases were selected as independent factors associated with poor EFS.
Factors associated with poor overall survival (OS) in the UA were CE, performance status (PS) ≥1, and high
sokal risk score at the start of 2-TKI therapy. In the MVA, only CE and a PS ≥1 were selected as independent
poor prognostic factors for OS. High hemoglobin level (≥12g/dL), 0% bone marrow blasts, previous cytogenetic
response to imatinib therapy, ≤90% Ph+ metaphases, and low sokal risk score were associated with the
achievement of a major cytogenetic response (MCyR) by 12 months of therapy with 2-TKI in the UA. In the
subsequent MVA for response, the lack of any cytogenetic response to imatinib therapy, anemia (hemoglobin
≤12g/dL) and ≥90% Ph+ metaphases at the start of 2-TKI therapy were selected as poor predictive factors for
12-month MCyR. Pts with 0, 1, 2, or 3 adverse factors had a 12-month probability of achieving a MCyR with 2-
TKI therapy of 85%, 79%, 35%, and 14%, respectively. Based on these findings, we developed a score model
that included the factors identified as independent predictive for a MCyR by 12 months of therapy with 2-TKI.
Three prognostic risk groups are proposed for the new score model: 1) low score (no adverse factors; 16% of
pts), in which pts have a 12-month probability of achieving a MCyR of 85%, after therapy with 2-TKI; 2)
intermediate score (1-2 adverse factors; 67% of pts), in which pts have a 12-month probability of achieving a
MCyR of 56%; and 3) high score (3 adverse factors; 17% of pts), in which pts have a 12-month probability of
achieving a MCyR of 14% (Table 2). This score model predicts significantly for EFS (p=0.003) with a trend for
OS (p=0.18). In conclusion, the outcome of pts post imatinib failure treated with 2-TKIs is dependent on
previous cytogenetic response to imatinib, absence of anemia, and disease burden at the start of therapy. Pts
with no previous cytogenetic response to imatinib therapy with anemia and high disease burden have a low
likelihood of responding to 2-TKI with poor EFS, and therefore should be offered alternative treatment options.
Table 1. Response to second generation TKIs
% Response
Overall Dasatinib Nilotinib
Parameter N=128 N=76 N=52 p-value
CHR 83 86 78 0.34
Cytogenetic response 70 70 71 0.86
Major 59 58 60 0.85
Complete 52 53 52 0.94
36-month EFS 58 64 48 0.03
36-month OS 82 85 78 0.27
CHR = complete hematologic response; EFS = event-free survival; OS = overall survival.
Table 2. Predicted outcome by number of risk factors (No cytogenetic response on imatinib, Hgb<12, %Ph>90
at the 2-TKI)
Risk (# risk factors) Number patients (%) MCyR 12m (%) OS
36m (%) EFS
36m (%)
Low (0) 20 (16) 85 95 85
Intermediate (1-2) 85 (67) 56 82 57
High (3) 21 (17) 14 72 38
CG=cytogenetic; CCGR=complete cytogenetic response; m=month; OS=overall survival; EFS=event-free
survival; NA=not applicable.
2199 Imatinib Long Term Effects (ILTE) Study: An International Study to
Evaluate Long-Term Effects in CML Patients
Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy Poster II
Sunday, December 6, 2009, 6:00 PM-8:00 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board II-176
Dong-Wook Kim1, Laura Antolini, PhD2*, François-Xavier Mahon, MD3*, Francois Guilhot, MD4, Michael
Deininger, MD, PhD5, Giuseppe Saglio, MD6*, Arnon Nagler, MD7*, Alessandro Rambaldi, MD8, Enrica Morra,
MD9, Elisabetta Abruzzese, MD10*, Francesco Di Raimondo, M.D.11*, Philipp le Coutre, MD12, Rafael Hurtado
Monroy, MD13, Muheez A Durosinmi, MD14*, Onno Leeksma, MD, DPhil15, Fabrizio Pane, MD16*, Stefania
Miglietta2*, Il-Young Kweon1*, Josy Reiffers, MD3*, Maria Grazia Valsecchi, PhD2* and Carlo Gambacorti-
Passerini, MD17
1Hematology, Catholic BMT Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of
Medicine, Seoul, South Korea
2Dept of Clinical and Preventive Medicine, Università Milano Bicocca, Monza, Italy
3Université Victor Ségalen Bordeaux - Institut Bergonié, Bordeaux, France
4Oncology, Hematology, and Cell Therapy, Clinical Investigation Centre CIC P 802 INSERM, Poitiers, France
5Knight Cancer Institute, Oregon Health & Science University, Portland, OR
6Laboratory of Medicine & Molecular Oncology, University of Turin San Luigi Gonzaga Hospital, Turin, Italy
7Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel
8Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy
9Department of Hematology, Niguarda Ca' Granda Hospital, Milan, Italy
10Hematology Unit, Tor Vergata University, Rome, Italy
11Department of Biomedical Sciences, University of Catania, Italy
12Department of Hematology and Oncology, Charité - Humboldt-Universitat, Campus Virchow, Berlin, Germany
13Hematology, Hospital Angeles del Pedregal, Mexico City, Mexico
14Haematology and Immunology, Obafemi Awolowo University, Ile-Ife, Nigeria
15Dept. of Hem./Med. Onc., Onze Lieve Vrouwe, Amsterdam, Netherlands
16Haematology Unit and Dep. of Biochemistry and Medical Biotechnology, CEINGE-Advanced Biotechnology,
University of Naples “Federico II”, Naples, Italy
17Hematology, Università Milano Bicocca and San Gerardo Hospital, Monza, Italy
Imatinib is an effective first line therapy for chronic myeloid leukemia (CML) and has substantially changed its
biological and clinical behavior. Durable complete cytogenetic responses (CCyR) were reported in the majority
of patients, with a rather benign side effect profile, despite the ‘off target’ inhibition of several other kinases,
including Kit, PDGFR and Lck. Since available information is largely based on sponsored trials and long-term
field studies are lacking, the ILTE study was conceived as an independent, academic, multicenter trial
supported by the Italian Drug Safety Agency (AIFA) and Regione Lombardia. ILTE is an international study on a
retrospective cohort and includes 31 centers in Europe, North/South America, Africa, Middle East and Asia;
therefore it is uniquely positioned to present a global picture of imatinib long-term effects. Consecutive patients
with Ph+ CML who started imatinib between 01 September 1999 and 31 December 2004 were eligible if they
were in CCyR after two years of imatinib treatment. Study endpoints were (a) survival, (b), serious adverse
events (SAE, including second cancers), (c) toxicities not qualifying as SAE (NSAE) but judged by the referring
physician as substantially impacting quality of life, (d) loss of CCyR, and (e) development of PCR negativity. A
total of 948 patients were enrolled, 88% of which met eligibility criteria after centers were visited and monitored.
The median age of eligible patients was 51 (range 18-92) years; 59% of patients were males and the median
follow-up was 4.0 years (excluding the first 2 years of treatment). As of Dec. 31 2008, 3255 person years were
available for analysis. Twenty one deaths were observed (only 6 of them [28%] caused by relapsed CML), with
a standardized rate of 0.6/100 person years and an observed/expected ratio of 0.7 (95% CI = 0.43-1.07, p=ns).
A total of 138 SAE were recorded (rate 4.2/100 person years, most frequent type “heart failure”), with 19.5%
being considered related to imatinib. Second cancers were documented in 29 patients (rate 0.9/100 person
years), with an observed/expected ratio of 1.02. Among the 761 NSAE recorded (rate 23.4/100 person years)
the most frequent types were cramps, asthenia,edema, skin fragility, diarrhea; 69% of them were considered
related to imatinib. A total of 18 patients (2.2 %) discontinued imatinib because of toxicities during the period of
observation. Forty patients lost CCyR, corresponding to a rate of 1.3/100 person years (1.0 in patients with
imatinib as first-line treatment, 1.4 in patients who were treated with imatinib >6 months after diagnosis), with
stable or increasing rates over time. Finally, 256 patients (36.0 %) developed durable (> 1 year) PCR negativity.
In conclusion, this report from ILTE shows that CML patients on imatinib die unfrequently of CML related
causes, do not appear to have substantially higher second cancer rates than the general population, have
mortality rates similar to an age/sex matched population and do not show new types of imatinib-related adverse
events. They also experience a low but steady rate of loss of CCyR and develop PCR negativity in
approximately 1/3 of cases. Follow-up and further analysis are ongoing. (Presented on behalf of the ILTE
Investigators group)
2194 A Phase I Study of the HDAC Inhibitor LBH589 in Combination with Imatinib
for Patients with CML in Cytogenetic Remission with Residual Disease
Detectable by Q-PCR
Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy Poster II
Sunday, December 6, 2009, 6:00 PM-8:00 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board II-171
Ravi Bhatia1, David S. Snyder2, Allen Lin3*, Jennifer Arceo1*, Linda Seymour1*, Michael Deininger4, Jerald
Radich5*, Suzette Blanchard1* and Stephen Forman3*
1City of Hope National Medical Center, Duarte, CA
2Division of Hematology/HCT, City of Hope National Medical Center, Duarte, CA
3Hem/HCT, City of Hope National Medical Center, Duarte, CA
4Oregon Health & Science University, Knight Cancer Institute, Portland, OR
5Fred Hutchinson Cancer Research Ctr., Seattle, WA
Imatinib mesylate (IM) is effective in inducing remission and improving survival in CML patients. However IM-
treated patients continue to harbor residual leukemia stem cells (Blood 101:4701, 2003). Most patients relapse
if treatment is discontinued, and it is generally recommended that treatment with IM be continued indefinitely.
The inability of IM to cure CML, the potential for side effects and the financial burden of life-long treatment
provide an impetus to develop approaches to eliminate residual leukemia stem cells. We have shown in
preclinical studies that treatment with the HDAC inhibitor LBH589 (LBH) combined with IM effectively eliminates
CML stem cells resistant to IM alone. The safety and MTD of LBH589 in combination with Imatinib has not been
previously evaluated. We have initiated a phase I, open label clinical trial to determine the safety and tolerability
of LBH589 given in combination with IM in CML patients, and to determine the MTD and dose-limiting toxicity
(DLT). CML patients in chronic phase (CP) treated with IM 400mg/d for >1 year with major or complete
cytogenetic response and residual disease on Q-PCR are eligible. LBH589 is administered in combination with
IM 400mg PO daily in 28 day cycles, with successive cohorts of patients receiving escalating doses of LBH 3
times a week (level 1: 10mg; level 2: 15mg; level 3: 20mg). Treatment is scheduled for 6 cycles of 28 days
each. Five patients have been enrolled thus far (Table). No dose limiting toxicity (DLT), defined as Grade 3
hematological or non-hematological toxicity in the first 28 days, was observed in 3 patients enrolled at dose
level 1. DLT (Grade 3 thrombocytopenia) was observed in 1 of the 2 patients enrolled at dose level 2. Other
toxicities included thrombocytopenia (Grade 3 [n=2]; Grade 1-2 [n=4]), hypophosphatemia (Grade 3 [n=1];
Grade 2 [n=2]), fatigue (Grade 1 [n=3]), hypocalcemia (Grade 1 [n=2] and Grade 1-2 GI symptoms (diarrhea
[n=2]; nausea [n=3]; anorexia [n=2]; vomiting [n=3]; constipation [n=1]). Of note, significant QTc prolongation
was not observed on intensive EKG monitoring. IM did not require to be held for any of these toxicities. Two
patients have completed 6 cycles of treatment, with one opting to receive an additional 3 cycles, 2 are currently
receiving treatment, and one withdrew after 1.5 cycles because of fatigue and GI symptoms. Bone marrow
aspirates for assessment of BCR-ABL status were performed at the end of cycles 3 and 6 of treatment. Q-PCR
analyses showed reduction in BCR-ABL levels in patient #2 (LBH 10mg) after 3 months, which was not
sustained at 6 months. Patient #4 (LBH 15mg), followed for 5 months so far, had undetectable BCR-ABL after 3
months of treatment. These results suggest that LBH589 can be safely administered in combination with IM.
Reduction in BCR-ABL levels was seen in two patients but the durability is unclear as yet. We are continuing
accrual of patients to define the MTD and safety of this combination.
Age/ Gender Prior TX CCR achieved on IM BCR-ABL at study entry LBH dose
level BCR-ABL after treatment Comments
1 46/F IM 30m 6m 0.07%(PB) 10mg 0.04% (PB 1.5m) Completed 1.5 cycles;
on IM 400mg QD.
2 65/F IFN 18m; IM 74m 4m 0.024%(BM) 10mg 0.0009% (BM 3m)
0.02% (BM 6m.) Completed 6 cycles; on IM 400mg QD
3 44/M IM 16m 3m 0.01%(BM) 10mg 0.01% (BM 3m and 6m) Completed 9
cycles; on IM 400mg QD
4 64/F IM 17m 6m 0.011%(BM) 15mg undetectable (BM 3m) On cycle 5.
5 48/M IM 13m MCR 7m 8.9%(BM) 15mg pending On cycle 1
1119 Weekend Drug Holiday of Dasatinib in CML Patients Not Tolerating
Standard Dosing Regimens. Reducing Toxicity with Maintained Disease Control
Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy Poster I
Saturday, December 5, 2009, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board I-141
Paul La Rosee, MD1*, Armin Leitner, MD2*, Philippe Martiat, MD3, Thomas Klag, MD1*, Samina Shazi, MD2*,
Anne Treschl, MD2*, Martin C Müller, MD2*, Thomas Schenk, MD1*, Benjamin Hanfstein2* and Andreas
Hochhaus, MD1
1Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany
2III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany
3Dept. of Experimental Hem., Institut Jules Bordet, Brussels, Belgium
Dasatinib (DA) is a multitargeted tyrosine kinase inhibitor (TKI) approved for 2nd line treatment of chronic
myelogenous leukemia (CML) patients after imatinib failure. DA-related toxicity mandates dose reduction in
selected patients beyond the labelled reduced continuous dosing. In chronic phase (CP) patients, intermittent
targeting of BCR-ABL by a once daily regimen reduces side effects with equal efficacy compared to the initially
explored twice daily regimen. Thus, considering the short half-life of DA (3-5 hours) additional treatment
interruptions to reduce the total weekly dose may not negatively affect treatment outcome while allowing
continued treatment with an effective drug. In a retrospective analysis 33 CML patients (pts; 20 m, 13 f, median
age 66 years, range 39-81) with intolerance (n=11) or resistance (n=22) to imatinib were investigated. Pts were
selected based on the toxicity-guided administration of a dose reduced dasatinib regimen and were treated with
an on/off regimen (3 to 5 days on, 4 to 2 days off) expecting a reduction of DA dependent off-target toxicity. Pts
were followed by routine hematologic and cytogenetic assessment, and molecular monitoring (quantitative
reverse transcriptase polymerase chain reaction, PCR) to safeguard clinical response to the altered drug
schedule. Further, resistant pts were regularly screened for BCR-ABL mutations. Median time since CML
diagnosis until start of DA treatment was 38 mo (range, 6-189). The median number of preceding treatment
modalities was 3 (range, 1-5). The median follow up of interval treatment was 23 mo (range, 3-41). 30 patients
were in CP, 2 in accelerated phase, and one in blast phase CML. 13/33 patients carried mutant BCR-ABL prior
to onset of DA-treatment. Non-exclusive reasons for dose reduction were hematologic toxicity (17/33; 51%), and
fluid retention (18/33, 55%), including 17 patients with pleural effusions. 27 patients (82%) suffered from grade
III/IV (CTC) side effects. The median weekly dose of the DA weekend holiday schedule was 500mg (range, 320-
500). During interval treatment, mean CTC grade for hematologic toxicity improved from grade 3.2 to 1.5 (p<0.
001), and for fluid retention from grade 2.9 to 1.6 (p<0.001). All but 2 pts (89%) affected by fluid retention, and
all but one patient suffering from hematologic toxicity (94%) achieved a lower CTC toxicity level by allowing drug
holiday. In 6/33 pts, resistance mutations (T315I x 2, F317L x 3, L248V) were recovered. For response
analysis, 2 pts were excluded due to early stem cell transplantation or loss of follow up. 13/31 (42%) did either
show transient improved molecular response or remained on stable BCR-ABL load over time. 3/31 progressed
to advanced phase CML. 18/31 (58%) pts showed the desired disease control according to established criteria
despite reduced total weekly DA doses either demonstrated by achieving an improved response level (12/31),
or keeping the response level achieved by continuous dosing (6/31). Fourteen of the 18 pts achieved or
maintained major molecular response (MMR) with 5 pts repeatedly tested negative by PCR. The remainder four
pts demonstrated response by achieving complete cytogenetic remission (CCyR, 2x) or reduced BCR-ABL load
<1% according to the international scale. Of note, 10/12 pts with improved response have been treated for a
minimum of 6 mo with continuous dosing DA regimens without having achieved the response level observed
after allowing drug holiday. We conclude that weekend treatment interruption allows continuation of DA
treatment for pts suffering from side effects. This retrospective analysis in pts resistant or intolerant to imatinib
with up to 5 preceding treatment modalities suggests good and in many cases even improved efficacy of
interval treatment compared to continuous dosing. These data mandate the initiation of clinical trials to
investigate alternative intermittent targeting regimens.
860 Phase II Multicentric Explorative Study of Intermittent Imatinib (IM)
Treatment (INTERIM) in Elderly Patients with Ph+ Chronic Myeloid Leukemia
(CML) Who Achieved a Stable Complete Cytogenetic Response (CCgR) with
Standard IM Therapy
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: New Trends in Management
Tuesday, December 8, 2009: 7:45 AM
293-296 (Ernest N. Morial Convention Center)
Domenico Russo1, Gianantonio Rosti2*, Giovanni Martinelli3*, Michele Malagola1, Salvatore Mirto4*, Diamante
Turri4*, Marco Gobbi5*, Ivana Pierri5*, Umberto Vitolo, MD6, Patrizia Pregno6*, Francesco Di Raimondo, M.D.
7*, Fabio Stagno7*, Robin Foà8*, Giuliana Alimena8*, Massimo Breccia8*, Francesco Nobile9*, Bruno
Martino9*, Alessandro Rambaldi, MD10, Tamara Intermesoli10*, Giuseppe Saglio, MD11, Giovanna Rege
Cambrin11*, Giuseppe Visani12*, Giuseppina Nicolini12*, Paolo de Fabritiis13*, Elisabetta Abruzzese13*,
Renato Fanin14*, Mario Tiribelli14*, Piero Galieni15*, Catia Bigazzi15*, Vincenzo Liso16*, Giorgina Specchia16,
Emanuele Angelucci17, Emilio Usala17*, Caterina Musolino18*, Sabina Russo18*, Gianluca Gaidano, MD19*,
Monia Lunghi19*, Francesco Lauria, MD20, Monica Bocchia21*, Francesco Rodeghiero, MD22, Anna D'Emilio,
MD22*, Giovanni Quarta23*, Mariella Girasoli23*, Alberto Bosi24*, Valeria Santini24*, Giuseppe Fioritoni25*,
Roberto Di Lorenzo26*, Chiara Colombi1*, Miriam Fogli3*, Marilina Amabile3*, Nicoletta Testoni3*, Antonio De
Vivo3* and Michele Baccarani3*
1Chair of Hematology, University of Brescia, Brescia, Italy
2Department of Hematology/Oncology "L. and A. Seràgnoli", University of Bologna and S.Orsola - Malpighi
Hospital, Bologna, Italy
3Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy
4Division of Hematology, Palermo, Italy
5Chair of Hematology, University of Genova, Genova, Italy
6Ematologia, ASOU San Giovanni Battista, Torino, Italy
7Department of Biomedical Sciences, University of Catania, Catania, Italy
8Dept. of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Rome, Italy
9Division of Hematology, Ospedali Riuniti, Reggio Calabria, Italy
10Hematology, Ospedali Riuniti, Bergamo, Italy
11Department of Clinical and Biological Sciences, University of Orbassano, Turin, Italy
12Department of Hematology, Ospedale San Salvatore, Pesaro, Italy
13Chair of Hematology, University Tor Vergata, Roma, Italy
14Chair of Hematology, University of Udine, Udine, Italy
15Divisione Ematologia, Ascoli Piceno
16Chair of Hematology, University of Bari, Bari, Italy
17Department of Hematology, Ospedale Oncologico "Armando Businco", Cagliari, Italy
18Hematology Section, Policlinico, University of Messina, Italy
19Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
20Hematology, University of Siena, Siena, Italy
21Department of Hematology and Transplants, University of Siena, Siena, Italy
22Department of Cell Therapy and Hematology, S. Bortolo Hospital, Vicenza, Italy
23Ematologia, Ospedale A. Perrino, Brindisi, Italy
24Chair of Hematology, University of Firenze, Firenze, Italy
25On behalf of GIMURELL and IIL, Hematology 2, AOU San Giovanni Battista, Torino, Italy
26Department of Haematology, "Spirito Santo" Civic Hospital, Pescara, Italy
Background: Elderly CML patients treated with Imatinib (IM) in early chronic phase (CP) have similar cytogenetic
response and survival compared with younger patients, but they show a lower compliance to standard IM
therapy (400 mg/day).
Aims: The aim of the study is to investigate if CCgR that has been achieved with standard (daily administration)
IM therapy can be maintained with the same dose of IM given intermittently (INTERIM).
Methods: The study population is represented by elderly patients ( 65 years old) with Ph+ CML and with
stable CCgR after at least 2 years of standard IM therapy (daily administration). IM is given at the same dose
that was given at the time of enrollment by the following intermittent schedule: 1 week on / 1 week off for the 1st
month; 2 weeks on / 2 weeks off for the 2nd and 3rd month; 1 month on / 1 month off from the 4th month
thereafter. In cases of loss of CCgR INTERIM was stopped and standard therapy (daily administration) was
resumed. After 12 months, the patients who are in continuous CCgR are advised to continue the intermittent
study schedule and to be followed indefinitely. The CgR status was evaluated at baseline (by conventional
cytogenetics on bone marrow and FISH on peripheral-blood) and every 3 months during the study (only by
FISH on peripheral-blood). If FISH (% of Ph+ cells) increased more than 1% in two consecutive examinations,
evaluation of marrow cells metaphases was performed to confirm the loss of CCgR and to check for additional
cytogenetic abnormalities. Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral
blood was due at baseline and every 3 months during the study and mutational analysis of ABL was performed
in case of loss of CCgR.
Results: One-hundred and fourteen patients have been considered eligible, but 17 (15%) refused to enter into
the protocol. Out of 97 enrolled patients, 87 started INTERIM, 5 patients (5%) went off the study for major
protocol violation before the 3rd month and, at present, 82 patients are ongoing. Of these 82 patients, 52, 30
and 11 completed the 3rd, 6th and 9th month, respectively. The preliminary results of the first 6 months are
here reported. The distribution of patients according to FISH results is shown in Fig. 1. Only 1/68 pts (at 6th
month) showed an increased >1% in Ph+ cells by FISH but he maintained a CCgR when checked by
conventional cytogenetic. As showed in Fig. 2, 96 to 87% of patients maintained a major molecular response
MMR (≤0,1) according to International Scale (IS).
Conclusions: This study is trying to test the minimum effective dose of Imatinib to maintain the CCgR in elderly
CML patients with stable CCgR. The preliminary results at 6 months do not show negative trends both for
cytogenetic and molecular response. Therefore, the study is ongoing and all patients are expected to complete
the trial time (12 months).
Fig. 1 Distribution of patients according to FISH
Fig. 2 Distribution of patients according to BCR/ABL transcript levels