ASH 2010 - pick of abstracts

2010 Dec 6, JS MacNeil

 

ORLANDO (EGMN) - The novel oral drug ponatinib may provide a much-needed therapeutic option for patients who develop resistance to at least two approved therapies for Philadelphia chromosome-positive chronic myeloid leukemia, a study has shown.

Results from an open-label phase I dose-escalation trial show major cytogenetic response rates as high as 66% in this heavily pretreated population.

In addition, all 11 patients with the dreaded T315I mutation that responds to none of the approved therapies had complete hematologic responses with ponatinib (also known as AP24534), and 9 had had a major cytogenetic response (8 of which were complete). The T315I subgroup included patients with other Philadelphia-positive (Ph+) blood cancers.

The trial followed laboratory studies that demonstrated ponatinib, a multitargeted tyrosine kinase inhibitor, can eliminate cells with "this very tough mutation" in the test tube, the lead author, Dr. Jorge Cortes, noted at a press briefing in advance of a presentation Dec. 6 at the annual meeting of the American Society of Hematology. The preclinical work also showed the new agent could prevent the emergence of cells with mutations that make them resistant to the existing CML drugs.

"So that made us think it could be a very valuable drug for these patients," said Dr. Cortes, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators enrolled 74 patients with refractory hematologic cancers in the trial, for which he reported data as of Oct. 15. The malignancies included acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), but the large majority of patients had Ph+ CML.

Nearly all (95%) of the Ph+ CML patients had experienced failures of more than two previous therapies, and 64%, more than three - these included imatinib (Gleevec, 96%); dasatinib (Sprycel, 89%); and nilotinib (Tasigna, 55%). All patients were assigned to daily doses of ponatinib in the trial, which identified the maximum tolerated dose as 45 mg/day. Men comprised just over half of the population, and the median age was 56 years (range, 26-85).

Among 55 evaluable patients, 38 had CML in the chronic phase. Of these, 36 (95%) had a complete hematologic response, and 25 (66%) had a major cytogenetic response; the latter included 20 (53%) patients with complete cytogenetic responses.

When 17 Ph+ patients were grouped together regardless of disease or stage of disease, 6 (35%) had a major hematologic response, and 4 (24%) had a major cytogenetic response, including 2 (12%) with a complete cytogenetic response.

The investigators projected that the sustained major cytogenetic response rate would be 78% at 1 year, with the median not yet reached.

Based on these results, Dr. Cortes announced that a phase II study called PACE has already been started to look at treating "all patients with Philadelphia-positive diseases in all stages of the disease."

At this point imatinib, dasatinib, and nilotinib have been approved as first- and second-line therapies for Ph+ CML, and at least two other drugs, bosutinib and omacetaxine mepesuccinate, are in development. Despite the success of the approved tyrosine kinase inhibitors, more drugs are needed, Dr. Cortes said, because they do not cure everyone.

"We need to recognize [that as good as] results so far are, we are not curing everybody," he said.

For physicians, the challenge will be to select the right drugs for each patient, he added in an interview. "We are going to have to be smart enough to learn how to integrate more of these options into treatment with algorithms to identify which patients are more likely to respond to one drug than another."

More drugs are needed, agreed Dr. Peter Emanuel, moderator of the press briefing, but the number and efficacy of drugs raises questions about which will continue to be used. "The burning question is whether imatinib will eventually become a historical drug," said Dr. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.

 http://www.oncologystat.com/news/Novel_CML_Drug_Active_After_Failures_of_Imatinib__Dasatinib__and_Nilotinib_US.html 

 

3431 Nilotinib Lowers the Incidence of BCR-ABL Mutations and Improves the Molecular Response Kinetics Compared with Imatinib in Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML)

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-210

Andreas Hochhaus, MD1, Giuseppe Saglio, MD, PhD2, Richard A. Larson, MD3, Dong-Wook Kim, MD, PhD4, Ian W. Flinn, MD, PhD5, Yeow-Tee Goh, MBBS, MD6, Pedro Enrique Dorlhiac-Llacer, MD7*, Kimmo Porkka, MD, PhD8, Mineo Kurokawa, MD, PhD9, Carmino DeSouza, MD, PhD10*, Yaping Shou, MD, PhD11*, Neil J. Gallagher, MD, PhD12, Ariful Haque13*, Hagop M. Kantarjian, MD14 and Timothy P. Hughes, MD, MBBS15

1Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
2Dept. of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
3The University of Chicago Medical Center, Chicago, IL
4Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
5Oncology, Sarah Cannon Research Institute, Nashville, TN
6Department of Clinical Research, Singapore General Hospital, Singapore, Singapore
7Hospital das Clinicas da FMUSP, São Paulo, Brazil
8Hematology Research Unit, Biomedicum Helsinki,, Helsinki University Central Hospital (HUCH), Helsinki, Finland
9Hematology/Oncology, University of Tokyo Hospital, Tokyo, Japan
10University of Campinas-SP, Campinas, Brazil
11Novartis Institutes for BioMedical Research, Cambridge, MA
12Oncology, Novartis Pharma AG, Basel, Switzerland
13Novartis Pharmaceuticals Corporation, East Hanover, NJ
14Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
15Department of Haematology, SA Pathology, Royal Adelaide Hospital, Adelaide, Australia

 

Background: In the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts) trial, nilotinib demonstrated superior efficacy vs imatinib in newly diagnosed pts. Here, we examined the kinetics of molecular response and BCR-ABL mutation status in pts from ENESTnd. 

Methods: Pts with CML-CP were randomized to receive nilotinib 300 mg twice daily (bid) (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg once daily (qd) (n = 283). BCR-ABL transcripts were quantified at baseline (BL) and every 3 months (mos); MMR was defined as ≤ 0.1% BCR-ABL on the International Scale (IS). Mutational testing of BCR-ABL was performed by direct sequencing at BL and at the occurrence of: (i) 5-fold increase in PCR levels, (ii) failure to achieve MMR at 12 mos, (iii) loss of MMR (≥ 0.1% BCR-ABLIS confirmed by a subsequent sample in association with a ≥ 5-fold rise in BCR-ABL from the lowest value achieved on study treatment), and (iv) end of treatment. Median follow-up was 18 mos. 

Results: During therapy, a more rapid decline in BCR-ABL levels was demonstrated in the nilotinib arms vs imatinib (Table). The median BCR-ABL levels for pts on nilotinib at 6 mos (both arms) were similar to those on imatinib at 18 mos. The median time to MMR among responders was also shorter on nilotinib (6, 8, and 10 mos in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively). Loss of MMR occurred in 14 (2%) pts (6 [2%], 5 [2%], and 3 [1%] in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms). Of the 14, none progressed to accelerated phase/blast crisis (AP/BC); only 1 of these pts showed a BCR-ABL mutation (M244V) in the imatinib arm, and 1 pt in the nilotinib 300 mg bid arm lost CCyR. Overall, 9 of 14 (64%) pts, including 8 of 11 on nilotinib, regained MMR within 6 mos on their assigned therapy. In 3 of these 9 pts who regained MMR, loss of MMR was concurrent with dose reduction, and MMR was regained at the time of dose re-escalation. Poor compliance may have contributed to fluctuations in BCR-ABL levels in some pts. At BL, no BCR-ABL mutations were found; 60 pts had polymorphisms which were equally distributed among the 3 arms. Mutational testing was triggered on therapy in 164, 171, and 199 pts in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively, most commonly due to lack of MMR at 12 mos. Approximately twice as many BCR-ABL mutations (16 [6%]) developed in the imatinib arm vs nilotinib arms (8 [3%] and 5 [2%] for 300 mg bid and 400 mg bid), and most of these were detected within the first 12 mos. The majority of mutations in the nilotinib arms were less sensitive (Y253H, E255K, F359V) or resistant (T315I) to nilotinib, while both nilotinib-sensitive and insensitive mutations were detected in the imatinib arm (Table). The T315I mutation emerged in 5 pts: 2 on nilotinib 300 mg bid, 1 on nilotinib 400 mg bid, and 2 on imatinib; two of these 5 pts discontinued therapy. Overall, 6 of 16 pts with mutations on imatinib progressed to AP/BC vs only 1 of 13 pts on nilotinib (Table). Minimum 24 month follow-up data for all pts will be presented.

Conclusions: Pts treated with nilotinib had faster and deeper molecular responses compared with imatinib. The incidence of new mutations was highest for imatinib, and most pts with mutations on nilotinib have not progressed with 18 mos of median follow-up. Loss of MMR was infrequent and was regained in the majority of cases without a change in therapy, and was not typically associated with subsequent treatment failure or the emergence of new mutations. Therefore, loss of MMR may not be an indicator for adjusting therapy, although close monitoring for further loss of response is warranted and mutation testing may be considered. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio: Novartis : Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.Larson: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kim: Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Flinn: Novartis: Research Funding. Goh: Novartis: Honoraria, Research Funding; Janssen Ciliag: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Dorlhiac-Llacer: Novartis:Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Wyeth: Research Funding. Porkka: Novartis:Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Shou: Novartis: Employment. Gallagher: Novartis Pharma AG:Employment, Equity Ownership. Haque: Novartis: Employment. Kantarjian: Novartis: Consultancy, Research Funding;Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.  

 

 

3427 Nilotinib 300 Mg Twice Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia In Chronic Phase: Updated Results of the ICORG 0802 Phase 2 Study with Analysis of  the GeneXpert System Versus IS BCR-ABL RQ PCR

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-206

Eibhlin Conneally, MB, MRCPI, FRCPath, PhD1, Ronan T Swords, MD, MRCPI, FRCPath2*, Francis J. Giles, MB, MD, FRCPI, FRCPath3, Mary Frances McMullin, MD4, Philipp le Coutre5, Stephen Langabeer6*, Marzena Wieczorkowska7*, Cliona McDowell8*, Brian Moulton7*, Karine Egan9* and Michael O'Dwyer, MD, FRCPath10

1Dept. of Hematology, St. James's Hosp., Dublin, Ireland
2Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX
3Medicine, Cancer Therapy and Research Center, CTRC at The UT Health Science Center, The Institute for Drug Development, San Antonio, TX
4Belfast City Hospital Department of Haematology, Queens University of Belfast, Belfast, United Kingdom
5Charite - Universitätsmedizin Berlin, Berlin, Germany
6Cancer Molecular Diagnostics, St. James's Hosp., Dublin, Ireland
7ICORG, Dublin, Ireland
8The N.I. Clinical Research Support Centre Education and Research Centre, Belfast
9Novartis Ireland Ltd., Dublin, Ireland
10Hematology, Univ. College Hosp. Galway, Galway, Ireland

 

Recently, early results of the ENESTnd phase III trial showing superiority of nilotinib over imatinib, led to accelerated approval of Nilotinib as initial treatment of ECP CML at a dose of 300mg BID.  Independently, since December 2008, ICORG, the All-Ireland Cooperative Oncology Research Group has been conducting an open-label, single stage, multicenter, phase II study (ClinicalTrials.gov NCT00809211) to investigate the safety and efficacy of nilotinib 300 mg BID in untreated, ECP, Ph-pos CML patients.

The primary endpoint is the CCyR rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a new rapid turnaround PCR system “GeneXpert” with IS BCR-ABL RQ-PCR. 

To date a total of 37 patients have been enrolled on the trial.  The median age of these 37 patients is 51 (range 20 –77); 50% have low risk Sokal score, 22% intermediate and 28% high risk. Median follow up is currently 8 months (range 1–17) with 25 patients evaluable for response following at least 3 months on study.

RESULTS: By intent to treat analysis the CCyR rate is 64% (16/25) at 3 months and 95% (19/20) at 6 months, with all patients actually tested Ph negative by 6 months.   By 6 months 12/20 patients have achieved MMR (60%).  This analysis includes 1 patient with variant transcripts and 2 patients bordering on MMR at 3 months who had insufficient RNA for analysis at 6 months.  While none of the patients have progressed on study, three patients are now off the study:  persistent grade 3 thrombocytopenia in one, persistent LFTS abnormalities in a second case and one death due to progressive multiple system atrophy, which was unrelated. 3 of 25 patients (12%) have undergone dose escalation to 400mg BID for suboptimal response.

The median daily dose was 600mg; 16/34 (47%) have interrupted nilotinib at least once with a median duration of interruption of 0.5 days. The dose of nilotinib at the last visit was > 300mg BID in 82% (28/34).  Haematologic toxicity was minimal with grade III thrombocytopenia seen in 2 patients (5%).  

Grade III non-haematologic toxicity included an elevated lipase in 6/36 (17%). The only other grade III toxicities noted were musculo-skeletal pain and an elevated ALT in 1 patient each.  Analysis of 71 follow-up paired samples from 21pts at 3 monthly intervals by "GeneXpert" and RQ-PCR showed an encouraging correlation between the methodologies. 

At 3 months the median BCR-ABL/ABL % was 0.45 as calculated by "GeneXpert" and 0.67 by IS RQ-PCR and at 6 months 0.06 and 0.01 respectively. However in individual patients, there was a trend for "GeneXpert" to underestimate Bcr-Abl/Abl % and therefore overestimate attainment of MMR.

CONCLUSION: In this preliminary analysis, nilotinib 300mg BID induces high rates of CCyR and MMR equivalent to those reported previously in the phase II and III studies of nilotinib in ECP CML. This trial provides independent confirmation that nilotinib 300mg BID is safe and effective treatment for ECP CML. "GeneXpert" provides rapid results both at diagnosis and follow–up and would be further enhanced by calculation of a conversion factor to the IS scale.

Disclosures: Conneally: Novartis: Honoraria. Giles: Novartis: Consultancy, Honoraria. Egan: Novartis: Employment.O'Dwyer: Novartis: Honoraria. 

 

 

 

3421 Safety and Efficacy of Dasatinib (DAS) Vs. Imatinib (IM) by Baseline Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-200

H. Jean Khoury, MD, FACP1*, Jorge E. Cortes, MD2, Hagop M. Kantarjian, MD3, Michele Baccarani, MD4*, Neil P. Shah, MD, Ph.D.5*, M. Brigid Bradley-Garelik, MD6*, David Dejardin7* and Andreas Hochhaus, MD8

1Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
2University of Texas M. D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Hematology-Oncology, University of Bologna, Bologna, Italy
5University of California, San Francisco, San Francisco, CA
6Bristol-Myers Squibb, Wallingford, CT
7Bristol-Myers Squibb, Braine l'Alleud, Belgium
8Universitätsklinikum Jena Klinik für Innere Medizin II, Jena, Germany

Background: BCR-ABL kinase inhibitors DAS, nilotinib and IM have become the primary treatment modality for patients (pts) with CML-CP. Pre-treatment comorbid conditions have been proposed to help select a second-line BCR-ABL inhibitor for IM-resistant CML-CP. The DASISION trial is a large Phase 3 trial comparing DAS with IM as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of DAS 100 mg once daily after a minimum follow-up of 12 months (Kantarjian, H, et al. N Engl J Med 2010;362:2260). This analysis assessed the impact of baseline comorbidities on safety and efficacy of these agents when used as initial therapy for CML-CP. 

Methods: 519 pts with newly diagnosed CML-CP were randomized to either DAS 100 mg once daily (n = 259) or IM 400 mg once daily (n = 260). Key exclusion criteria included serious uncontrolled medical disorders or active infections; uncontrolled or serious cardiovascular disease; prior or concurrent malignancy; inadequate hepatic or renal function; and ECOG performance status of ≥ 3. Pts were analyzed according to the number (0, ≥ 1 and ≥ 2) and type of baseline comorbidity (allergic, dermatologic, diabetes, endocrine-metabolic, gastrointestinal, hematologic-lymphatic, hepatobiliary, hyperlipidemia, musculoskeletal, renal and respiratory), and age (< 46, 46-65 and > 65 y). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed across these groups. Cardiovascular comorbidities were analyzed separately and are not included here.  

Results: Across the 2 treatment arms, 74% of the pts had ³ 1 baseline comorbidity and 47% had ³ 2. The distribution of comorbidities including allergic (n = 61), dermatologic (n = 62), diabetes (n = 31), endocrine/metabolic (n = 98), gastrointestinal (n = 176), hematologic/lymphatic (n = 57), hepatobiliary (n = 56), hyperlipidemia (n = 41), musculoskeletal (n = 150), neoplasia (n = 17), renal (n = 33) and respiratory (n = 72) was balanced across the 2 arms. Proportions of pts across 3 Hasford risk groups were similar between pts with baseline comorbidity and those without.  Safety profiles of DAS and IM in pts with and without baseline comorbidities were comparable (Table). Proportions of pts with at least 1 dose interruption or dose reduction were also similar with or without any comorbidity (Table). Pts with ³ 2 comorbidities and pt grouped by comorbidity type including diabetes mellitus, hepatobiliary conditions and hyperlipidemia also had generally similar safety profiles.  In both arms, the 12-mo rates of CCyR and MMR were similar (Table). In DAS-treated pts with diabetes (n = 18), hepatobiliary conditions (n = 32) and hyperlipidemia (n = 22), CCyR rates were 67, 78 and 96%, respectively; the respective MMR rates were 44, 56 and 59%. IM pts with diabetes (n = 13), hepatobiliary conditions (n = 24) and hyperlipidemia (n = 19) had CCyR rates of 69, 75 and 79%, respectively; and MMR rates of 15, 29 and 32%, respectively. In DAS-treated pts, CCyR rates were 88% for pts aged < 46 y (n = 128), 78% for those aged 46-65 y (n = 111) and 85% for those aged > 65 y (n = 20); the corresponding MMR rates were 45, 47 and 50%, respectively. The corresponding IM age groups (n = 111, 125 and 24, respectively) had CCyR rates of 70, 70 and 83%, respectively; and MMR rates of 26, 30, 29%, respectively. Safety profiles were generally similar across age groups in both treatment arms, except that fluid retention rates in pts aged < 46, 46-65 and > 65 y were 13, 25 and 35%, respectively, for DAS; and 34, 45 and 67%, respectively, for IM. 

Conclusions: The presence of baseline comorbidities appeared to have no effect on the safety and efficacy of either DAS or IM as initial therapy for CML-CP.

Disclosures: Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani: Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Shah: Bristol-Myers Squibb, Novartis and Ariad:Membership on an entity’s Board of Directors or advisory committees. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding.  

 

 

 

3415 Targeting XIAP and ARC (apoptosis repressor with caspase recruitment domain) Overcomes Imatinib Resitance In Blast Crisis CML Cells

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-194

Bing Carter, Ph.D.1, Duncan H. Mak, M.S.2*, Wendy D. Schober1*, Marina Konopleva, MD, PhD3*, Jorge E. Cortes, MD4, Hagop M. Kantarjian, MD5, Erich Koller6*, Ziwei Huang7*, John C. Reed, MD, PhD8 and Michael Andreeff, M.D., Ph.D.9

1Molecular Hematology & Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Molecular Hematology & Therapy, Department of Leukemia, MD Anderson Cancer Center, Houston, TX
3Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Leukemia, MD Anderson Cancer Center, Houston, TX
6Isis Pharmaceuticals, Carlsbad, CA
7Pharmacology, SUNY Upstate Cancer Research Institute, Syracuse, NY
8Sanford-Burnham Medical Research Institute, LA Jolla, CA
9Molecular Hematology & Therapy, Department of Leukemia and Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX

 

The advent of imatinib, a Bcr-Abl tyrosine kinase inhibitor (TKI) has revolutionized the treatment of patients with CML. Development of resistance and limited activity in blast crisis (BC) CML are evolving problems facing this therapy.

We found that XIAP, a potent caspase inhibitor, is highly expressed in CML cells, in both, cell lines and patient samples. Treatment with imatinib deceased XIAP levels in imatinib-sensitive KBM5 but much less so in imatinib-resistant KBM5STI571 cells (harboring T315I mutation) suggesting that XIAP expression in CML is regulated at least in part via Bcr-Abl and that targeting XIAP may promote cell death in CML cells by circumventing imatinib resistance.

To test this, we treated BC CML cells with XIAP antisense oligonucleotide (ASO) and with SMAC mimetic ABT-10 and found that inhibition of XIAP induced apoptotic cell death with similar efficacy in KBM5 cells and KBM5STI517 cells (EC50=6.3±0.3 μM and 8.4±0.4 μM at 48 hours, respectively for ABT-10). However, we noted that inhibition of XIAP by ASO induced the expression, in both KBM5 and KBM5STI571 cells, of apoptosis repressor with caspase recruitment domain (ARC) in both mRNA and protein levels but not the expression of Bcl-2 protein.

ARC is a unique antiapoptotic protein. It acts through inhibiting caspases and antagonizing the activity and function of p53 and Bax. Therefore, its induction may antagonize the effect of XIAP downregulation. Indeed, inhibition of both XIAP and ARC by ASO induced significantly more cell death than inhibiting either protein alone in both KBM5 and KBM5STI cells. Furthermore, we demonstrated that XIAP inhibition induced-apoptosis was enhanced by imatinib in KBM5, but not in KBM5STI cells. Interestingly, inhibition of Bcr-Abl tyrosine kinase by imatinib not only decreased XIAP, but also suppressed ARC levels in KBM5 but had minimal effects on the levels of these proteins in KBM5STI571 cells and enforced expression of the Bcr-Abl p185 fusion protein (in HL-60 cells) greatly increased both XIAP and ARC levels. This induction was inhibited by imatinib suggesting that ARC is also a downstream target of Bcr-Abl tyrosine kinase. Therefore, imatinib enhancing XIAP inhibition induced-apoptosis in KBM5, not KBM5STI cells can be explained at least in part by its ability to decrease XIAP and ARC levels.

In conclusion, XIAP is highly expressed in CML cells and upregulated by Bcr-Abl. Targeting XIAP promotes death of BC and TKI resistant CML cells. Results suggest that XIAP is a potential target in BC and TKI resistant CML cells and that XIAP inhibition-induced apoptosis is enhanced by imatinib in TKI sensitive cells and by ARC inhibition independent of cellular responses to TKIs. Inhibition of XIAP and ARC as a novel therapeutic strategy in CML warrants further investigation.

Disclosures: Koller: Isis Pharmaceuticals: Employment  

 

 

3414 Poor Adherence Is the Main Reason for Loss of CCyR and Imatinib Failure for CML Patients On Long Term Imatinib Therapy

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-193

Amr R Ibrahim1*, Dragana Milojkovic2*, Marco Bua1*, Jamshid S Khorshad1*, Richard Szydlo1*, Lina Eliasson3*, Letizia Foroni, MD, PhD1, Alistair Reid1*, Hugues de Lavallade1*, Katayoun Rezvani, MD, PhD1*, John M. Goldman, DM, FRCP, FRCPath, FMedSci1*, Jane Apperley, MBChB, FRCP, FRCPath1* and David Marin, MD, FRCP1

1Haematology Department, Hammersmith Hospital, Imperial College London, London, United Kingdom
2Department of Hematology, Hammersmith Hospital, Imperial College London, London, United Kingdom
3Department of Practise and Policy, The School of Pharmacy, London, United Kingdom

We have previously shown that adherence to imatinib therapy is the single most important factor determining the degree of molecular response achieved by CML patients (Marin et al,  JCO 2010). We now study the relation between adherence to imatinib and the probabilities of losing CCyR and of imatinib failure in patients receiving long term therapy.

We measured the adherence to imatinib in 87 consecutive chronic phase CML patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment, all of whom were in complete cytogenetic response (CCyR). Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS, see below) and patients were followed subsequently for a median of 15 months.  Data from the patients were censored in March 2010, when our previous work was published, to ensure that the results of this study were not influenced by possible changes in a patient's behaviour. 

MEMS is an electronic device fitted into the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of kinase domain mutations and the following factors assessed at diagnosis: demographic data, hemoglobin, leukocytes, Sokal risk group, BCR-ABL1 transcript type, hOCT1 transcript levels, and the presence of the 1236C>T polymorphism in ABCB1. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate.

Adherence was defined as the quantity of imatinib actually taken divided by the amount prescribed expressed at a percentage. The median adherence was 97.6% range 24-100%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%).  During the follow up 7 (8%) patients lost their CCyR, and 12 (13.8%) discontinued the imatinib therapy (7 because of loss of CCyR, 2 because of failure to achieve MMR and 3 because of side effects). In multivariate analysis the adherence rate was the only independent predictor for loss of cytogenetic response (RR=0.95, p=0.0001) and discontinuation of imatinib therapy (RR= 0.97, p=0.009).  When we categorized the adherence rate as (≤90% or >90%) we found that at 18 months the 23 patients with an adherence rate ≤90% had a higher probability of losing the CCyR (26.8% vs 1.5%, p=0.0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, p=0.006) than the 64 patients with an adherence rate >90% (Figure). In summary we have shown that poor adherence to imatinib is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long term therapy.

Disclosures: Marin: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.

 

 

3413 Evaluation of Residual CD34+/Ph+ Stem Cells In Chronic Myeloid Leukemia Patients In Complete Cytogenetic Response during First Line Nilotinib Therapy

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-192

Monica Bocchia1*, Marzia Defina1*, Micaela Ippoliti1*, Elisabetta Abruzzese2*, Fausto Castagnetti3*, Mario Tiribelli4*, Gianantonio Rosti5*, Massimo Breccia, MD6*, Malgorzata Monika Trawinska2*, Rosaria Crupi1*, Lara Aprile1*, Marzia Salvucci7*, Claudia Baratè8*, Antonella Gozzini9*, Michela Rondoni1*, Alfonso Zaccaria7*, Giuliana Alimena, MD6*, Valeria Santini9*, Giorgina Specchia10, Renato Fanin4*, Alessandro Gozzetti1* and Francesco Lauria, MD1*

 

Introduction Imatinib mesylate is highly effective in inducing rapid hematologic and cytogenetic responses in the vast majority of chronic myeloid leukemia (CML) patients.  Yet, discontinuation of treatment is associated with disease relapse probably due to the persistence of resistant leukemic stem cells representing a reservoir of the disease. On this regard it has been reported that BCR-ABL positive progenitor cells can still be detected in patients in complete cytogenetic response (CCyR) after short term of imatinib treatment (Bhatia R, et al. Blood. 2003;101:4701-4707) but  also after a stable long lasting CCyR (Bocchia M, et al. Leukemia. 2008;22:426-428). Compared to imatinib, the second generation Tyrosin Kinase Inhibitor (TKI) nilotinib appears to eradicate more rapidly the bulk of CML cells, inducing high rate of CCyR and major molecular response (MMolR) after a very short period of treatment (78% CCyR and 52% MMolR  at 3 months) (Rosti G, et al. Blood. 2009;114(24):4933-8). Despite nilotinib is a more potent TKI, it didn’t appear to be more effective in eliminatingin vitro CML progenitors than imatinib (Konig H, et al Leukemia. 2008;22:748-755). Up to date no data evaluating the persistence of Ph+ stem cells in early chronic phase CML patients during first line treatment with nilotinib have been reported.

Patients, materials and methods We investigated the presence of residual CD34+/Ph+ cells in 24 CML patients in CCyR during first line nilotinib treatment. Patients were enrolled in 2 clinical trials (GIMEMA CML0307 and CAMN107A2303) and evaluation of residual leukemic stem cells was performed during a routine bone marrow aspirate after receiving specific patients informed consent.  Bone marrow purified CD34+ cells were evaluated for BCR-ABL fusion gene by fluorescent in situ hybridization (FISH) analysis. A minimum of 100 interphase nuclei of purified CD34+ cells was considered optimal for FISH analysis.

Results: All 24 patients have been treated exclusively with nilotinib since diagnosis (17/24 at 400mg bid; 5/24 at 300mg bid; 2/24 at 400mg/day). At the time of analysis all 24 patients were in CCyR for a median time of 27 months (range 6-29) after being treated for a median time of 30 months (range 9-30) with this second generation TKI.  Regarding molecular response 20/24 (83%) were in MMolR while only 1/24 (4%) was in CMolR.  Harvest, purification and subsequent FISH analysis of bone marrow CD34+ cells was optimal in 15/24 (63%) patients, suboptimal in 5/24 (21%) patients (less than 100 interphase nuclei analyzed) and not adequate in 4/24 (16%) patients (less than 50 interphase nuclei).  With respect to leukemic stem cells, residual CD34+/Ph+ cells were found only in 1/20 (5%) evaluable patients. Of note, in this patient 140 CD34+ interphase nuclei were analyzed and only 1 was found bcr-abl positive (0.7%).

Conclusion Our study shows for the first time that in patients in CCyR during front line Nilotinib treatment residual CD34+/Ph+ stem cells are very rarely detected.  These results quite differ from what was previously found in imatinib treated patients (Bocchia M, et al. Leukemia. 2008;22:426-428). In fact in the present series, only 1/20 (5%) patients treated with nilotinib in CCyR for a median time of 27 months showed residual CD34+/Ph+ cells, while in our prior study residual leukemic CD34+ cells were still detectable in 14/31 (45%) imatinib treated patients in stable CCyR (median of 39 months).  Despite the limited number of patients studied, this novel evidence may support the better short term clinical results observed with nilotinib as first line treatment in CML.

Disclosures: Rosti: Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.  

 

 

 

3412 One Year of Intermittent Imatinib (IM) Treatment (InterIM) Maintains the Complete Cytogenetic Response (CCgR) Previously Achieved with Standard IM Therapy In Elderly (≥ 65 years) Ph+ CML Patients – EudraCT Number 2007-005102-42, ClinicalTrials.Gov NCT 00858806

Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 6, 2010, 6:00 PM-8:00 PM

Hall A3/A4 (Orange County Convention Center) 
Poster Board III-191

Domenico Russo1*, Giovanni Martinelli2, Michele Malagola, MD1, Chiara Colombi1*, Giantonio Rosti3*, Marilina Amabile3*, Miriam Fogli3*, Diamante Turri4*, Salvatore Mirto4*, Marco Gobbi5*, Ivana Pierri5*, Umberto Vitolo6*, Patrizia Pregno7*, Enrica Morra8, Ester Pungolino8*, Francesco Di Raimondo9*, Fabio Stagno, MD9*, Robin Foà10*, Giuliana Alimena10*, Massimo Breccia10*, Francesco Nobile11*, Bruno Martino11*, Alessandro Rambaldi12, Tamara Intermesoli12*, Giuseppe Saglio13, Giovanna Rege Cambrin13*, Giuseppe Visani14*, Giuseppina Nicolini14*, Paolo de Fabritiis15*, Elisabetta Abruzzese15*, Renato Fanin16*, Mario Tiribelli16*, Piero Galieni17*, Catia Bigazzi17*, Giorgina Specchia18*, Vincenzo Liso, MD19*, Emanuele Angelucci20, Emilio Usala20*, Caterina Musolino, MD21*, Sabina Russo22*, Gianluca Gaidano23*, Monia Lunghi23*, Francesco Lauria24*, Monica Bocchia24*, Francesco Rodeghiero25*, Anna D'Emilio25*, Alberto Bosi26*, Valeria Santini26*, Giovanni Quarta27*, Mariella Girasoli27*, Giuseppe Fioritoni28*, Roberto Di Lorenzo28*, Nicoletta Testoni3*, Antonio De Vivo3*, Simona Soverini3*, Ilaria Iacobucci2*, Michele Baccarani3* and Michele Baccarani29*

The phase II 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) after at least 2-years standard IM therapy (any dose between 300 and 800 mg/day) was started in April 2008 and closed for the enrollment in August 2009,since more than 78 patients required by statistics were included into the study. The main objective of the study was to investigate if after 12 months (trial time) the CCgR achieved with standard (daily administration) IM therapy could be maintained with  InterIM . For this purpose, the CgR status was assessed by Interphase Fluorescence In Situ Hybridization (I-FISH) on peripheral blood (≥ 200 cells counted) every 3 months. When I-FISH (% Ph + nuclei) increased more then 1%, chromosome banding analysis (CBA) on bone marrow was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities (ACA). At the present time, out of the 95 patients who were enrolled, 82 patients were evaluable and out of them 77 (94%), 73 (89%), 71 (87%) and 70 (85%) completed 3, 6, 9 and 12 months of the treatment program, respectively. Therefore, the great majority of patients completed the study core and at the end of 2010 all the patients are expected to complete the trial time (12 mo). During the first 12 months of InterIM, 1% to 11% of the evaluable patients at 3, 6, 9 and 12 months showed  an I-FISH >1% Ph+ nuclei (Figure 1).

 

Figure 1 - Distribution of patients according to I-FISH

Totally, eleven (13%) out of 82 patients treated with InterIM showed an I-FISH  >1% and they were checked by CBA on bone marrow (Figure 2). Out of them only 3 cases, that means 4% of the 82 evaluable patients, lost the CCgR and resumed standard IM therapy (daily administration), but none completed 3 months of therapy. All the patients lost the MMR and increased several folds the BCR-ABL transcript levels. Two pts had a low risk Sokal and one a high risk; age was 66, 69, 77 years; time from diagnosis was 29, 91 and 100 months; duration of IM therapy was 29, 83 and 84 months; the IM dose was 400mg in all cases.

Figure 2- Cytogenetic and molecular response in 11 cases who showed I-FISH >1% + nuclei and who were checked by CBA on bone marrow. Black boxes shows the 3 cases who lost the CCgR

 

 As concern as molecular response, 99% of the patients had a major molecular response (MMR=<0.001-0.1 BCR-ABL/ABLISX 100) at the baseline. The proportion of the patients who maintained the MMR after 3, 6, 9 and 12 months of InterIM was 95%, 92%, 91%, 84%, respectively. Interestingly, we found a weak but significant correlation between the % of BCR-ABL + nuclei and the BCR-ABL transcript levels in the patients who completed the trial time (12 mo) (r=0.27; p=0.001).

In conclusion, the results of the InterIM study core (12 months), clearly show that Intermittent Imatinib (IM) treatment (InterIM) is sufficient to maintain the complete cytogenetic response (CCgR) previously achieved with standard IM therapy in elderly (≥ 65 years) Ph+ CML patients. The risk to loose the CCgR has been very low (4%), while the benefit either in terms of reduction of IM  dose and of costs of therapy or in terms of compliance (data not shown) was very high.

Acknowledgments: This work was supported in part by CML-Leukemia Net and Progetto Regione Lombardia.  

 

 

668 Evaluating the Response to Imatinib In Philadelphia-Positive Chronic Myeloid Leukemia (Ph+ CML): The Value of Major Molecular Response (MMolR) at 12 Months

Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: Rethinking Therapy Targets and Prognostic Factors

Monday, December 6, 2010: 4:45 PM

Valencia A (Orange County Convention Center)

Michele Baccarani1*, Gianantonio Rosti2*, Giovanni Martinelli2, Fausto Castagnetti2*, Francesca Palandri2*, Gabriele Gugliotta2*, Marilina Amabile2* and Nicoletta Testoni2*

1Department of Hematology/Oncology, University of Bologna, Bologna, Italy
2Department of Hematology/Oncology "Seràgnoli", University of Bologna, Bologna, Italy

 

The cytogenetic response is a confirmed early surrogate marker of the outcome of Ph+ CML patients treated with imatinib (Baccarani et al, JCO 2009;27:6041-51). Many reports and reviews highlight the value of MMolR, defined as a BCR–ABL value equal/less than 0.1% on the International Scale (Hughes et al, Blood 2006;108:20-37). The European LeukemiaNet recommendations use the BCR-ABL level for the definition of optimal response at 12 months (achievement of MMolR) and suboptimal response at 18 months (less than MMolR), but not for the definition of failure (Baccarani et al, JCO 2009; 27: 6041-51). As the prognostic value of achieving a MMolR may increase with the introduction of 2nd generation tyrosine kinase inhibitors (TKIs) in the frontline treatment of Ph+ CML, we have reviewed and compared the cytogenetic and molecular data of 4 company–sponsored studies and 4 independent investigator–sponsored studies, for a total number of 2466 patients treated frontline with imatinib (Table 1). The CCgR rates at 12 months ranged between 49% and 88% (median 66%). The MMolR rates at 12 months ranged over a wider range, between 15% and 65% (median 33%). The ratio CCgR/MMolR ranged between 1.31 and 1.90 (median 1.60) in 5 out of 8 studies, while in the other 3 studies (Hammersmith, ENESTnd, and DASISION) the ratio was much higher, ranging between 2.35 and 4.00. Comparing Hammersmith, ENESTnd and DASISION studies to the other 5 studies (IRIS, TOPS, ELN, GIMEMA, and TIDEL), the CCgR rates were similar (median 64% vs. 67%, range 45-73% vs. 58-88%), while the MMolR rates were lower (median 22% vs. 40%, range 15-31% vs. 26-65%). These data cannot be used to argue that a lab, a dose of imatinib, or a study, is “better or worse” than the others, but higlight the consistency of CCgR worldwide and warns from overemphasizing the MMolR rate at 12 months for response evaluation and for treatment adaptation or modification.

 

* Euro Score; (1) O’Brien et al, NEJM 2003;348:994-1004; (2) Hughes et al, NEJM 2003; 349: 1423-32; (3) De Lavallade et al, JCO 2008; 26:3358-63;  (4) Cortes et al, JCO 2009; 28:424-430; (5) Saglio et al, NEJM 2010;362:2251-9; (6) Kantarjian et al, NEJM 2010; 362:2260-70; (7) Hughes et al, Blood 2008;112:3965-73; (8) Castagnetti et al, JCO 2010;28: 2748-54; (9)Baccarani et al, Blood 2009; 113:4497-4504

Molecular studies sere performed: IRIS at 3 labs (Hammersmith, Adelaide; Seattle), Hammersmith at 1 lab, TIDEL at 1 lab (Adelaide), ELN at Bologna and many other labs, TOPS at 3 labs (Naples, Adelaide and Seattle), GIMEMA at 1 lab (Bologna), ENESTnd and DASISION at 1 lab (Portland)