Discontinuation of second generation (2G) tyrosine kinase inhibitors (TKI) in chronic phase (CP)-chronic myeloid leukemia (CML) patients with stable undetectable BCR-ABL transcripts (916)

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia - Therapy II

Tuesday, December 11, 2012: 8:15 AM

A411-A412, Level 4, Building A (Georgia World Congress Center)

Delphine Rea, MD, PhD^1*, Philippe Rousselot, MD, PhD^2*, François Guilhot, MD³, Michel Tulliez, MD^4*, Franck E. Nicolini, MD, PhD⁵, Agnès Guerci-Bresler, MD^6*, Laurence Legros, MD, PhD^7*, Martine Gardembas, MD^8*, Stephane Giraudier, MD, PhD^9*, Gaelle Guillerm, MD^10* and Francois-Xavier Mahon, MD, PhD^11*

¹Service des Maladies du Sang, Hopital Saint Louis AP-HP, Paris, France
²Hôpital André Mignot, Le Chesnay, France
³CIC Inserm 0802, CHU de Poitiers, Poitiers, France
⁴Hematology department, Hôpital Henri Mondor, Creteil, France
⁵Centre Hospitalier Lyon Sud, Pierre Benite, France
⁶Hematology department, CHU Brabois, Vandoeuvre les Nancy, France
⁷Service d'Hematologie Clinique, Hopital de l'Archet CHU Nice, Nice, France
⁸Hematology department, CHU d'Angers, Angers, France
⁹Hematology department, Hôpital Henri-Mondor, Créteil, France
¹⁰Hematology, Hôpital Augustin Morvan, Brest, France
¹¹Laboratoire d'hematologie, Universite Victor Segalen, Bordeaux, Pessac, France

Background: TKI have proven remarkably successful against CML. Despite this progress, current recommendation is to never stop therapy. However, prospective trials such as STIM and CML8 suggest that imatinib may be stopped in patients with deep and sustained molecular responses (Mahon et al, Lancet Oncol. 2010; Ross et al, Haematologica 2012). Here, we report on the feasibility of 2G-TKI discontinuation.

Methods: Adult CP-CML patients on dasatinib or nilotinib without previous allogeneic transplantation or progression to advanced phase CML were proposed treatment discontinuation provided that (1) TKI treatment duration was at least 36 months (2) BCR-ABL transcripts were undetectable for at least 24 months, with at least 20 000 amplified copies of the control gene. The primary objective was treatment-free stable major molecular response (MMR: BCR-ABL/ABL internationally standardized (IS) ratio ≤ 0.1% IS). BCR-ABL transcripts were quantified in local laboratories monthly during the first 12 months, every 2-3 months during the 2^nd year and every 3-6 months thereafter. Molecular relapse was defined by the loss of MMR and triggered therapy resumption. The study is ongoing and 42 patients currently agreed to stop dasatinib (53%) or nilotinib (47%). Data as of August 1, 2012 are reported, focusing on the subgroup of 34 patients with a minimum follow-up of 6 months (median 14, range 7-33).

Results: Median age was 58 (34-81), 56% of patients were females (n=19). Sokal risk group was low in 56% (n=19), intermediate in 24% (n=8), high in 11% (n=4) and unknown in 9% (n=3). Twelve patients (35%) received interferon prior to TKI therapy, 25 (74%) were treated with 2G-TKI upfront (n=2) or after imatinib intolerance (n=25) and 9 (26%) received 2G-TKI due to suboptimal response/resistance. The median time since diagnosis was 87 months (31-218), the median time since TKI initiation was 79 months (30-133), the median duration of 2G-TKI therapy was 35 months (21-72) and the median duration of undetectable BCR-ABL transcripts was 27 months (21-64). At last follow-up, the 12-month probability to remain in stable MMR was 58.3% (95% CI, 41.5%-75%). The median time to MMR loss was 4 months (1-25). Importantly, no hematologic relapse was observed and none of the patients progressed to advanced phase CML. Since in imatinib discontinuation trials, different definitions for molecular relapse were used, we also calculated the rate of relapse according to STIM (detectable BCR-ABL on 2 consecutive tests with at least 1 log increase between the 2) and CML8 (detectable BCR-ABL on 2 consecutive tests at any level). The corresponding 12-month probabilities were 55.8% (95% CI, 39.2%-72.6%) according to STIM and 44.1% (95%CI, 27.4%-60.8%) according to CML8. We searched for factors possibly associated with treatment-free stable MMR. Patients treated with 2G-TKI first line or after imatinib intolerance had a significantly higher probability of stable MMR than those who were switched to 2G-TKI because of suboptimal response/resistance (12-month rate 67.3% (95% CI, 48.6%-86%) versus 33% (95% CI; 2.5%-64.1%), p=0.02). Gender, age, prior IFN exposure, 2G-TKI type and treatment duration were not found to have any impact but caution is needed due to the small size and heterogeneity of this series. Treatment was resumed in 15 patients after a median time of 5 months (2-29). The same 2G-TKI used prior to discontinuation was reintroduced in all but 1 patient, due to tolerance issues. The median follow-up since treatment resumption was 9 months (0-27). At last follow-up, MMR was regained in all 13/15 evaluable patients and undetectable BCR-ABL in 10/13. Eighteen patients with stable MMR remained off-therapy at last follow-up (median 16 months, range: 7-33), among which 7 with stable undetectable BCR-ABL and 11 with weakly detectable BCR-ABL on 1 or more occasions.

Conclusions: 2G-TKI may be safely discontinued in CP-CML patients with long-lasting undetectable BCR-ABL under strict molecular monitoring conditions, especially in patients with prior imatinib intolerance or treated with 2G-TKI as first line therapy. In patients with prior imatinib suboptimal response/resistance, strategies to improve outcome are needed. The recurrence of a low level of detectable residual disease below the MMR threshold after 2G-TKI withdrawal may not automatically herald CML relapse and may not preclude the possibility to remain treatment-free.

Disclosures: Rea: BMS, Novartis, Teva: Honoraria. Rousselot: BMS, Novartis: Research Funding. Guilhot: Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Tulliez: BMS, Novartis: Honoraria. Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Guerci-Bresler: Novartis, BMS: Speakers Bureau. Legros: BMS, Novartis: Honoraria. Gardembas: Novartis: Speakers Bureau. Giraudier: Novartis: Speakers Bureau. Mahon: Novartis, BMS: Consultancy, Research Funding.

Outcome of patients with chronic myeloid leukemia in chronic phase (CML-CP) based on early molecular response and factors associated with early response: 4-year follow-up data from ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients) (167)

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia - Therapy I

Sunday, December 9, 2012: 5:30 PM

A411-A412, Level 4, Building A (Georgia World Congress Center)

Andreas Hochhaus, MD¹, Timothy P. Hughes, MD, MBBS², Giuseppe Saglio³, François Guilhot⁴, Haifa Kathrin Al-Ali, MD^5*, Giantonio Rosti⁶, Chiaki Nakaseko, MD, PhD⁷, Carmino Antonio De Souza, PhD⁸, Charisse Kemp^9*, Xiaolin Fan, PhD^10*, Albert Hoenekopp, MD^11*, Richard A. Larson, MD¹² and Hagop M. Kantarjian, MD¹³

¹Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany
²Department of Haematology, SA Pathology, Royal Adelaide Hospital, Adelaide, Australia
³Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy
⁴Inserm cic 802, CHU de Poitiers, University Hospital, Poitiers, France
⁵University of Leipzig, Leipzig, Germany
⁶Department of Hematology and Medical Oncology, University of Bologna, Bologna, Italy
⁷Department of Hematology, Chiba University Hospital, Chiba, Japan
⁸University of Campinas, Campinas, Brazil
⁹Novartis Pharmaceuticals Corp, East Hanover, NJ
¹⁰Novartis Pharmaceuticals Corporation, East Hanover, NJ
¹¹Novartis Pharma AG, Basel, Switzerland
¹²University of Chicago, Chicago, IL
¹³MD Anderson Cancer Center, Houston, TX

Background: In the ENESTnd study, nilotinib significantly reduced progression to accelerated phase/blast crisis (AP/BC) and demonstrated superior rates of deep molecular response vs imatinib. Data from ENESTnd demonstrated that significantly more patients achieved early molecular response of both < 10% and < 1% BCR-ABL^IS at both 3 and 6 months on nilotinib vs imatinib. Here, we report landmark analyses based on BCR-ABL transcript levels at 3 and 6 months using data with a minimum follow-up of 3 years and also provide data on factors associated with poor early molecular response; data based on longer follow-up of 4 years will be presented.

Methods: The nilotinib 300 mg twice daily (BID; n = 282) and imatinib 400 mg once daily (QD; n = 283) arms from ENESTnd were used for this analysis. Patients were grouped based on BCR-ABL transcript levels of ≤ 1%, > 1% to ≤ 10%, and > 10% at 3 months (n = 258 and n = 264 patients with available PCR samples at 3 months in the nilotinib and imatinib arms, respectively) and at 6 months (n = 257 and n = 256 patients with available PCR samples at 6 months in the nilotinib and imatinib arms, respectively). Rates of major molecular response (MMR; ≤ 0.1% BCR-ABL^IS) and molecular response with a 4.5-log reduction in BCR-ABL transcript levels (MR^4.5, ≤ 0.0032%^IS)  as well as rates of progression-free survival (PFS) and overall survival (OS) were evaluated among patients grouped according to their BCR-ABL transcript levels at 3 and 6 months. Data on selected baseline characteristics and dose intensity were also assessed.

Results: Among evaluable patients at 3 months, 9% of patients (n = 24) in the nilotinib arm vs 33% (n = 88) in the imatinib arm had BCR-ABL transcript levels of > 10%; among evaluable patients at 6 months, 3% of patients (n = 7) in the nilotinib arm vs 16% (n = 40) in the imatinib arm had BCR-ABL transcript levels of > 10%. Patients with a BCR-ABL transcript level of > 10% had a lower probability of future MMR or MR^4.5 as well as poorer PFS and OS compared with patients who had BCR-ABL transcript levels ≤ 10% at 3 months (Table). Results were similar based on 6-month landmark analyses. In patients with > 10% BCR-ABL transcript levels at 3 months, the average dose intensity of nilotinib within the first 3 months was 474 mg/day compared with 600 mg/day for patients with ≤ 10% BCR-ABL transcript levels; the average dose intensity of imatinib within the first 3 months was the same (400 mg/day) for patients with both ≤ 10% and > 10% BCR-ABL levels at 3 months (Table). Patients with > 10% BCR-ABL transcript levels at 3 months were also more likely to have high Sokal risk, larger spleen size, and additional chromosomal abnormalities compared with patients with ≤ 10% BCR-ABL transcript levels at 3 months. Other factors associated with early response and further data on long-term outcomes are being assessed and will be presented with a minimum follow-up of 4 years.

Conclusions: Fewer patients in the nilotinib arm vs the imatinib arm had BCR-ABL transcript levels > 10% at 3 and 6 months. Reasons for poor early response appeared to be related, at least in part, to baseline factors and dose intensity. Early molecular response at 3 and 6 months correlated with future MMR and MR^4.5as well as an increased probability of PFS and OS. Nilotinib frontline therapy allows more patients to achieve deeper responses earlier, associated with improved long-term outcomes vs imatinib.

* Response and outcomes were evaluated in patients who had available PCR samples at 3 or 6 months. Patients who achieved the target response within 3 or 6 months were excluded from the respective analysis of response outcomes; patients who had events or were censored within 3 or 6 months were excluded from the respective analysis of time-to-event outcomes.

Disclosures: Hochhaus: BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hughes: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Guilhot: Celgene: Consultancy; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali: Novartis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria. Rosti: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau. Kemp: Novartis Pharmaceuticals Corp: Employment. Fan: Novartis Pharmaceuticals Corp: Employment. Hoenekopp: Novartis Pharma AG: Employment, Equity Ownership. Larson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian: Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

A pivotal phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial (163)

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia - Therapy I

Sunday, December 9, 2012: 4:30 PM

A411-A412, Level 4, Building A (Georgia World Congress Center)

Jorge E. Cortes, MD¹, Dong-Wook Kim, MD², Javier Pinilla-Ibarz, MD, PhD^3*, Philipp le Coutre, MD⁴, Ron Paquette, MD, PhD^5*, Charles Chuah, MD^6*, Franck E Nicolini, MD, PhD⁷, Jane Apperley⁸, H. Jean Khoury⁹, Moshe Talpaz, MD¹⁰, John F. DiPersio, MD, PhD¹¹, Daniel J. DeAngelo, MD, PhD¹², Elisabetta Abruzzese¹³, Delphine Rea, MD, PhD^14*, Michele Baccarani, MD¹⁵, Martin C Muller^16*, Carlo Gambacorti-Passerini, MD¹⁷, Stephane Wong, PhD¹⁸, Stephanie Lustgarten^19*, Victor M. Rivera, PhD¹⁹, Tim Clackson, PhD¹⁹, Christopher D. Turner, MD, FAAP¹⁹, Frank G Haluska, MD, PhD¹⁹, Francois Guilhot, MD²⁰, Michael W. Deininger, MD, PhD²¹, Andreas Hochhaus, MD^22*, Timothy Hughes²³, John M Goldman, MD²⁴, Neil Shah, MD, PhD²⁵, Hagop M Kantarjian, M.D.²⁶ and The PACE Study Group^19*

¹Department of Leukemia, University of Texas, MD Anderson cancer center, Houston, TX
²Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
³H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
⁴Hematology/Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany
⁵Ronald Reagan UCLA Medical Center, University of California, Los Angeles, CA
⁶Hematology, Singapore General Hospital/Duke-NUS Graduate Medical School, Singapore, Singapore
⁷Pierre Benite, Centre Hospitalier Lyon Sud, Pierre Benite, France
⁸Imperial College, Department of Haematology, Hammersmith Hospital, London, United Kingdom
⁹Emory Winship Cancer Institute, Atlanta, GA
¹⁰Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
¹¹Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO
¹²Dana-Farber Cancer Institute, Boston, MA
¹³Ospedale S. Eugenio, Rome, Italy
¹⁴Hematology department, Hôpital Saint Louis, Paris, France
¹⁵Dept. Hematology and Medical Oncology, University of Bologna, Bologna, Italy
¹⁶Universitätsmedizin Mannheim, III. Med. Klinik, Mannheim, Germany
¹⁷Dept. of Hematology, Università  Milano Bicocca and S. Gerardo Hospital, Monza, Italy
¹⁸MolecularMD Corp, Portland, OR
¹⁹ARIAD Pharmaceuticals, Inc., Cambridge, MA
²⁰CIC Inserm 0802, CHU de Poitiers, Poitiers, France
²¹Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
²²Universitätsklinikum Jena, Jena, Germany
²³Institute of Medical and Veterinary Science, Adelaide, Australia
²⁴Department of Hematology, Imperial College, London, United Kingdom
²⁵Department of Medicine, University of California San Francisco, San Francisco, CA
²⁶Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX

Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure‑based design with optimal binding to the BCR‑ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR‑ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial.

Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP‑CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)‑CML/Ph+ALL R/I (N=48), BP‑CML/Ph+ALL T315I (N=46). Five patients (3 CP‑CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months.

Results: Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3‑28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP‑CML and AP‑CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP‑CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan‑Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP‑CML, 42% in AP‑CML, 35% in BP‑CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR‑ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients’ younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug‑related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug‑related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis).

Conclusions:Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented.

Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Research Funding; Ariad, Pfizer, Teva: Consultancy. Kim: Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz: Novartis, BMS: Research Funding, Speakers Bureau. le Coutre: Novartis and BMS: Honoraria. Paquette: ARIAD: Consultancy. Chuah: Novartis, Bristol-Myers Squibb: Honoraria. Nicolini: Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Apperley: Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz: Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Abruzzese: BMS, Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Rea: Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani: ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller: ARIAD: Consultancy. Wong: MolecularMD Corp: Employment, Equity Ownership. Lustgarten: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera: ARIAD: Employment, Equity Ownership. Clackson: ARIAD: Employment, Equity Ownership. Turner: ARIAD: Employment, Equity Ownership. Haluska: ARIAD: Employment, Equity Ownership. Guilhot: ARIAD: Honoraria. Hochhaus: ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman: Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah: ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.