Post ASH speaker abstracts 2018

CML

Abstracts to support presentations from Deepti Radia, Mhairi Copland and Priyanka Mehta

Clinical and Molecular Characterization of Clonal Chromosomal Abnormalities Appearing in Philadelphia-Negative Metaphases of Chronic Phase CML

Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy

Number: 47
Program: Oral and Poster Abstracts
Type: Oral
Session: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Novel Targets and CML Stem Cell Biology

Ghayas C. Issa, MD1*, Hagop M. Kantarjian, MD1, Feng Wang, PhD2*, Graciela Nogueras González3*, Gautam Borthakur, MD1, Guilin Tang, MD4*, Carlos E. Bueso-Ramos, MD, PhD4, Rashmi Kanagal-Shamanna, MD4, Juliana Elisa Hidalgo Lopez, MD4, Chong Zhao4*, Marcus Coyle2*, Koichi Takahashi, MD2, Preetesh Jain, MBBS, MD, DM, PhD5, Farhad Ravandi, MBBS6, Tapan Kadia, MD1, Guillermo Garcia-Manero, MD1, Elias J. Jabbour, MD 7, Andrew Futreal, PhD2* and Jorge E. Cortes, MD8

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
5Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
7Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
8Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX

 

Background: Clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph-) emerge as patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKI). The clinical significance of CCA/Ph- remains unclear specifically among pts treated with second generation TKI. Very little is known about the molecular abnormalities associated with them.

Methods: We conducted a retrospective analysis of pts enrolled on prospective, single-institution frontline trials for CML-CP. Of the 598 pts enrolled, 279 pts (46%) were treated with imatinib, 126 (21%) with nilotinib, 143 (23%) with dasatinib and 50 (8%) with ponatinib. CCA/Ph- were defined as abnormalities present in ≥2/20 Philadelphia-negative (Ph-) metaphases or if present in one metaphase in ≥2 cytogenetic assessments. The clinical outcomes of pts with CCA/Ph- were compared to a control group without additional chromosomal abnormalities (ACAs). We performed targeted deep sequencing (median depth 490x) on a pilot study from 10 pts with various CCA/Ph- (panel of 295 genes recurrently mutated in hematological malignancies). Single nucleotide variants (SNV) and small insertions and deletions (indels) were called against virtual normal sequence developed in-house. An automatic pipeline was used to filter and annotate raw variants, and then select non-polymorphism, protein-coding changing mutation, thus identifying high confidence driver mutations.

Results: CCA/Ph- occurred in 58 pts (10%) and the most common were – Y in 25 (43%) and trisomy 8 in 7 pts (12%). Most CCA/Ph- appeared within the first year of the start of the TKI (median 6 months, range 3-78 months). CCA/Ph- were transient and were detected in 2 or less time points in 36/58 cases (62%). The median number of Ph-negative metaphases containing CCA/Ph- per analysis was 5/20 (range 1-20). We further categorized CCA/Ph- into those where – Y was the only clonal abnormality, and all others. Pts who developed CCA/Ph- were significantly older than those without ACAs (median age 59 vs 47; P<0.001). Specifically, pts with –Y CCA/Ph- were the oldest (median age 64; P<0.001), followed by those with non-Y CCA/Ph- (median age 52; P=0.003) when compared to those without ACAs (median age 47). Four pts with ACAs in Ph+ metaphases who subsequently developed CCA/Ph- were excluded from response and survival analyses. Response to TKI therapy was similar for pts with CCA/Ph- and those without ACAs. With a median follow-up for survivors of 7.6 years (range 0.2-14.7 years), we found that pts with non –Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS) compared to those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = 0.02), EFS (68% vs 86%, P = 0.02), TFS (76% vs 94%, P < 0.01) and OS (79% vs 94%, P = 0.03). In a multivariate analysis, non –Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio (HR) of 2.81 (95% CI 1.15-6.89, P = 0.02). However, this prognostic impact was not statistically significant when achieving BCR-ABL < 10% at 3 months was included in the analysis (Table 1).

A total of 46 high-confidence driver mutations in 18 genes in 10/10 (100%) pts with CCA/Ph- were identified (Figure 1). Median number of driver mutations was 2.5 (range 1-9). ASXL1 frameshift mutation was detected in all examined pts (10/10 pts) mostly at low variant allelic frequency (VAF) with a median VAF of 1.6% (range 0.7% – 4.2%). Mutations were also commonly detected in PTPN11 (7/10 pts). Mutations in PTPN11 have been reported in about 4% of pts with acute myeloid leukemia (Papaemmanuil et al. NEJM 2016). Mutations in DNMT3A (R635Q) and ABL (Y253H, associated with resistance to imatinib) were observed in the same case in addition to ASXL1. In this cohort, the observed mutation rate is higher than what is expected in CP-CML when comparing to published literature (Kim et al. Blood 2017). Sequencing of a control cohort from pts with deep molecular response without ACAs is ongoing.

Conclusion: In conclusion, non –Y CCA/Ph- are associated with decreased survival when emerging in pts with chronic phase CML across various TKIs. Preliminary results from deep sequencing indicate a higher than expected rate of mutations in CP-CML pts with CCA/Ph- compared to those without ACAs, mostly detected at low VAF.

“Duration of Deep Molecular Response” Has Most Impact on the Success of Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia – Results from the EURO-SKI Trial

Result Type: Paper
Number: 313
Presenter: Susanne Saussele
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Therapy: Treatment Discontinuation, Dose Reduction, and Prognostic Indicators

Susanne Saussele, MD 1, Johan Richter, MD, PhD2*, Joelle Guilhot, PhD3, Henrik Hjorth-Hansen, MD4, Antonio Medina de Almeida, MD, PhD5*, Jeroen J. W. M. Janssen, MD6*, Jiri Mayer, MD7, Perttu Koskenvesa, MD8*, Panayiotis Panayiotidis, MD, PhD9*, Ulla Olsson-Strömberg, MD, PhD10*, Juan Luis Steegmann, MD, PhD11, Hanne Vestergaard, MD12*, Hans Ehrencrona, MD, PhD13*, Veli Kairisto14*, Kateřina Machová Poláková, PhD15*, Martin Müller, MD16*, Satu Mustjoki, MD, PhD8,17, Marc G. Berger, MD, PhD18*, Philippe Rousselot, MD19,20,21*, Martine Escoffre-Barbe, MD22*, Gabriel Etienne, MD, PhD23*, Jolanta Dengler, MD24*, Françoise Rigal-Huguet, MD25*, Nikolas von Bubnoff, MD26*, Hana Klamova, MD15*, Edgar Faber, MD27*, François Guilhot, MD3*, Kourosh Lotfi, MD28*, Delphine Rea, MD29, Tim H. Brümmendorf, MD30, Gorgine de Greef, MD31*, Leif Stenke, MD32,33*, Franck Emmanuel Nicolini, MD, PhD34,35,36, Laurence Legros, PhD, MD37*, Andreas Burchert, MD38, Jaroslava Voglová, MD39*, Aude Charbonnier, MD40*, Emmanuel Gyan, MD-PhD41, Maria-Elisabeth Goebeler, MD42*, Peter E. Westerweel, MD43*, Andreas Hochhaus, MD44, Markus Pfirrmann45* and Francois-Xavier Mahon, MD, PhD46

1Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
2Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
3INSERM CIC 1402, CHU de Poitiers, Poitiers, France
4Department of Hematology, St Olavs Hospital, Trondheim, Norway
5Instituto Portugues de Oncologia de Lisboa de Francisco Gentil, Lisbon, Portugal
6Department of Hematology, VU University Medical Center, Amsterdam, Netherlands
7Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
8Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Comprehensive Cancer Center, Helsinki, Finland
9Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
10Department of Hematology, University Hospital Uppsala, Uppsala, Sweden
11Servicio de Hematologia y Grupo 44 IIS-IP, Hospital Universitario de la Princesa, Madrid, Spain
12Department of Hematology, Odense University Hospital, Odense, Denmark
13Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden
14Department of Clinical Chemistry, Turku University Central Hospital, Turku, Finland
15Institute of Hematology and Blood Transfusion, Prague, Czech Republic
16Institute for Hematology and Oncology (IHO GmbH), Mannheim, Germany
17Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
18Hématologie Biologique and EA 7453 CHELTER, CHU Estaing and Université Clermont Auvergne, Clermont-Ferrand, France
19Department of Hematology and Oncology, Centre Hospitalier de Versailles, INSERM UMR 1173, Université Versailles Saint-Quentin-en-Yvelines, Université Paris Saclay, Le Chesnay, France
20Hôpital de Versailles, Le Chesnay, France
21Fi-LMC group, Pessac, France
22Service d’Hématologie Adulte, CHU de Rennes, Rennes, France
23Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Bordeaux, France
24Onkologische Schwerpunktpraxis Heilbronn, Heilbronn, Germany
25Centre Hospitalier Universitaire (CHU) de Toulouse, Toulouse, France
26Innere Medizin I Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation, Universitätsklinikum Freiburg, Freiburg, Germany
27Department of Hemato-Oncology, Palacký University Olomouc, Faculty of Medicine and Dentistry, Olomouc, Czech Republic
28Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
29Service d’Hématologie adulte et Centre d’Investigation Clinique Hôpital Saint Louis, Paris, France
30Uniklinik RWTH Aachen, Aachen, Germany
31Department of Hematology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands
32Division of Hematology, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
33Division of Hematology, Department of Medicine, Karolinska Institute, Stockholm, Sweden
34Hématologie Clinique, Centre Léon Bérard, Lyon, France
35Hématologie clinique 1G, Centre Hospitalier Lyon Sud, Pierre Benite, France
36INSERM U1052, Centre de recherche en cancérologie de Lyon (CRCL), Lyon, France
37Hematology department, Centre Hospitalier Universitaire de Nice, Nice, France
38Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie, Universitätsklinikum Marburg, Marburg, Germany
394th Department of Internal Medicine – Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Králové, Czech Republic
40Paoli-Calmettes Institute, Marseille, France
41Hématologie et Thérapie Cellulaire, CHU de Tours, Tours, France
42Medizinische Klinik und Poliklinik, Universitätsklinikum Würzburg, Würzburg, Germany
43Internal Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands
44Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
45Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany
46Bergonié Cancer Institute INSERM Unit 916, University of Bordeaux, Bordeaux, France

 

Background: The advent of tyrosine kinase inhibitors (TKI) has decisively improved the survival of patients with chronic myeloid leukemia (CML). Many patients achieve deep molecular response (DMR), a prerequisite for cessation of TKI therapy. The goal of the EURO-SKI trial was to assess the safety and feasibility and to define precise conditions for stopping treatment.

Methods: Chronic-phase CML patients without prior failure to any TKI, treated for at least three years and in DMR for at least one year were eligible for stopping TKI. DMR was defined as MR4 (detectable BCR-ABL1 on International Scale (IS) ≤ 0.01% or undetectable BCR-ABL1 in samples with ≥ 10,000 ABL1 or ≥ 24,000 GUS transcripts, respectively). Molecular responses were assessed by real-time quantitative PCR (RQ-PCR) at designated standardized laboratories. Primary outcome was molecular recurrence- (MRecFS) and treatment-free survival (MRecTFS) defined by staying at least in major molecular remission (MMR, BCR-ABL (IS) < 0,1%) without restart of therapy. MRecTFS was estimated with the Kaplan-Meier method.

For the prognostic logistic regression analysis of the endpoint “MRecFS status after 6 months”, candidate variables were age at diagnosis and at TKI discontinuation, sex, Sokal, Euro, EUTOS, and ELTS risk scores, and, alternatively, any variable part of any of the scores, previous IFN treatment, duration of TKI treatment, time to DMR while under TKI treatment, and DMR duration until discontinuation of TKI. Prognostic results were examined in an independent validation sample.

Results: 821 patients (48% female, median age 60 years at study entry, range 19-90) were recruited, 755 patients were assessable for the estimation of MRecTFS. 371 (49.1%) lost MMR after TKI cessation, 13 restarted TKI in MMR, and 4 died in MMR. MRecTFS was 60% at 6 months (95% confidence interval (CI): 56-63%) and 49% at 24 months (CI: 45-52%). For 224 (29.7%) patients a grade 1-2 and for 9 patients a grade 3 TKI withdrawal syndrome was reported.

After treatment restart, so far 321 (86%) and 302 (81%) of 373 patients re-achieved MMR and MR4, respectively. Median time to regain MMR and MRwas 3 and 4 months, respectively.

In a prognostic model, of 448 patients (186 relapses after 6 months, 42%), 77 (17%) received IFN pre-treatment before imatinib was started. As IFN-pretreatment >1.5 years had significant positive influence on MRecFS, these patients were omitted in the prognostic model. In 405 imatinib treated patients TKI-treatment duration and DMR duration were significantly (p<0.005) correlated with MRecFS at 6 months. The minimal p-value approach identified a threshold of 5.8 years for imatinib-therapy duration and 3.1 years for DMR duration distinguishing two groups with 17% difference in MRecFS at 6 months. However, as MR4 duration before TKI discontinuation was part of duration of imatinib treatment, both parameters were strongly correlated. The influence of the variable “duration of imatinib treatment before MR4 achievement” was not significant (p=0.50).

Considering all candidate variables including the new variable “duration of imatinib treatment before MR4achievement” for multivariate modelling, MR4 duration and duration of imatinib treatment before MR4 achievement were weakly negatively correlated (Spearman’s rank correlation coefficient: -0.29), and only MR4 duration remained significant (p=0.0009; duration of treatment before MR4: p=0.0921

The validation sample consisted of 195 patients (73 relapses after 6 months, 37%). MR4 duration had the same odds ratio of 1.13 (CI: 0.98-1.29) as in the learning sample but were not significant anymore (p=0.08).

Conclusion: EURO-SKI outlines important preconditions which can be employed as guidance for stopping criteria. Criteria with improved impact for successful stopping could be defined using a prognostic modeling to predict MRecFS at 6 months in a large cohort of patients who stopped imatinib. Best cut-off was defined by 3.1 years for MR4 duration and 5.8 years for imatinib-therapy duration whereas the later was less important.

Apart from the two cut-offs, an almost linear increase in MRecFS probability per additional year on treatment / in MR4 for patients treated first-line with imatinib could be demonstrated. In conclusion, for imatinib therapy, a minimal total treatment duration of 6-years is suggested of which the patient should have been in MR4 for at least 3 years before stopping.

Dasatinib Discontinuation in Patients (Pts) with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) and Stable Deep Molecular Response (DASFREE)

Result Type: Paper
Number: 314
Presenter: Neil Shah
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Therapy: Treatment Discontinuation, Dose Reduction, and Prognostic Indicators

Neil P. Shah, MD, PhD1, Valentín García Gutiérrez, PhD2, Antonio Jiménez-Velasco, MD3*, Sarah M Larson, MD4*, Susanne Saussele, MD 5, Delphine Rea, MD6, François-Xavier Mahon, MD, PhD7, Moshe Levy, MD8, María Teresa Gómez-Casares, MD, PhD9*, Fabrizio Pane, MD10, Franck-Emmanuel Nicolini, MD, PhD11, Michael J. Mauro, MD12, Oumar Sy, PhD13*, Patricia Martin Regueira13* and Jeffrey H. Lipton, PhD, MD, FRCPC14*

1UCSF School of Medicine, San Francisco, CA
2Servicio Hematologia y Hemoterapia, Hospital Universitario Ramon y Cajal, Madrid, Spain
3Hospital Universitario Carlos Haya, Malaga, Spain
4David Geffen School of Medicine at UCLA, Los Angeles, CA
5Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
6Hématologie, Hôpital Saint-Louis, Paris, France
7Université Bordeaux Segalen, Bordeaux, France
8Baylor University Medical Center at Dallas, Dallas, TX
9Hospital Universitario De Gran Canaria Dr., Negrin, Spain
10Università degli Studi di Napoli, Federico II, Italy
11Hématologie clinique 1G, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
12Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York, NY
13Bristol-Myers Squibb, Princeton, NJ
14Cancer Clinical Research Unit, Princess Margaret Cancer Centre, University of Toronto, Ontario, Canada

 

Background: A current focus of CML research is achievement of sustained, deep molecular response (DMR) on TKIs, with the goal of stopping therapy. In clinical trials of TKI discontinuation, approximately 50% maintain their response (Saussele. Leukemia. 2016). Dasatinib is a suitable option for pts considering treatment-free remission (TFR) because it induces high rates of early, deep, and sustained responses (Cortes. JCO.2016). Here, we report results from all pts enrolled in the phase 2 DASFREE study, investigating TFR in the largest population of pts discontinuing dasatinib in the 1st line and beyond.

Methods: DASFREE (CA180-406/NCT01850004) is a phase 2, open-label, single-arm study in adults with CML-CP on dasatinib for ≥2 yr as 1st-line or subsequent therapy. Eligible pts also had dasatinib-induced DMR (MR4.5 or BCR-ABL1 ≤0.0032% on the International Scale) confirmed at a local lab for ≥1 yr prior to enrollment, with a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 mo of starting dasatinib. During the screening phase, MR4.5 was confirmed at a central lab twice within 3 mo prior to dasatinib discontinuation. BCR-ABL1 was monitored centrally after discontinuation every mo in the 1st yr, then every 3 mo. If major molecular response (MMR) was lost, pts resumed dasatinib at the previous dose. The primary endpoint is rate of MMR 1 yr after dasatinib discontinuation. Secondary endpoints include BCR-ABL1 kinetics, event-free survival (EFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase [AP/BP] CML), rate of transformation to AP/BP, progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and MMR after reinitiating dasatinib. This analysis includes assessment of the entire cohort of 84 enrolled pts as of July 2017 (minimum follow-up of 6 mo). Analysis of data for all pts with ≥12 mo of follow-up will be presented.

Results: As of October 2016, 84 pts were enrolled (Sokal scores: 63% low, 29% intermediate, 6% high, 2% unknown; no pts had prior interferon; 38 pts on 1st-line dasatinib). At the time of this analysis, 63 pts had ≥12 mo of follow-up after discontinuation. Median dasatinib dose at discontinuation was 100 mg/d (range 20-150). EFS at 1 yr was 49% (95% CI 37, 59; Figure). Forty-three of 84 pts (51%) lost MMR. Median time from discontinuation to loss of MMR was 4 mo (range 1-10). All 43 pts who lost MMR restarted dasatinib, 41 (95%) of whom have regained MMR after re-treatment (1 pt withdrew from study and was lost to follow-up, 1 pt does not have sufficient follow-up). Median time to regain MMR was 2 mo (range 1-4). Median time from CML diagnosis to discontinuation was 72 mo (range 29-156) in pts without loss of MMR after discontinuation and 69 mo (range 29-244) in pts with loss of MMR after discontinuation. Pts maintaining MMR had a median time of 72 mo (range 28-154) on prior TKIs; pts losing MMR had a median time of 67 mo (range 28-221) on prior TKIs. Median time on prior TKIs was shorter in pts treated with 1st-line dasatinib: 46 mo (range 28-89) in pts who maintained MMR and 34 mo (range 28-87) in pts who lost MMR. In a multivariate analysis, no relationship was found between RFS and duration of prior TKI and line of therapy. No transformation events or deaths were observed. Most AEs occurred off-treatment, although not all were attributed to withdrawal events. Musculoskeletal disorders were reported in 23 pts (27%) off-treatment, and in 8 pts (with 14 events) these were considered withdrawal syndrome. Withdrawal events occurred after a median of 3 mo (range <1-6) after discontinuation; 9 of these events resolved after a median of 3 mo (range 1-9). Interestingly, hypertension occurred in 6 pts (7%) off-treatment. There were no AEs leading to discontinuation from the trial.

Conclusions: Data from DASFREE support the feasibility of TFR in pts with CML-CP in DMR treated with dasatinib in the 1st line and beyond. In this largest analysis of pts with CML-CP in DMR who discontinued dasatinib, approximately 50% of pts maintained MMR. With a minimum follow-up of 6 mo, 41 of 43 pts who lost MMR quickly regained their response after therapy was reinitiated. There was a small number of pts with symptoms of dasatinib withdrawal. Data for all enrolled pts with ≥12-mo of follow-up will be presented.

Persistence with Generic Imatinib for Chronic Myeloid Leukemia: A Matched Cohort Study

Result Type: Paper
Number: 315
Presenter: Adi Klil-Drori
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Therapy: Treatment Discontinuation, Dose Reduction, and Prognostic Indicators

Adi J. Klil-Drori, MD1, Hui Yin, MSc2*, Laurent Azoulay, PhD2*, Alexa Del Corpo3*, Michael Harnois4*, Michel-Olivier Gratton4*, Lambert Busque, MD5 and Sarit Assouline, MD6

1Segal Cancer Center, Jewish General Hospital, Montreal, QC, Canada
2Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
3Jewish General Hospital, Montreal, QC, Canada
4Hopital Maisonneuve Rosement, Montreal, QC, Canada
5University of Montreal, CIUSSS de l’Est de l’Ile de Montreal, Maisonneuve-Rosemont Hospital, Montreal, Canada
6Segal Cancer Center, Lady Davis Institute, McGill University Jewish General Hospital, Montreal, QC, Canada

 

Background: Generic imatinib (GI) has been approved for use in Canada and other countries based on bioequivalence. A high rate of GI discontinuation has been reported to be related to intolerance (Islamagic E, et al. Clin Lymphoma Myeloma Leuk. 2017;17:238) but no clinical studies have been conducted to determine whether GI is clinically comparable to branded imatinib (BI) for chronic myeloid leukemia (CML). In Quebec, GI was approved and reimbursed in early 2013 and was mandated to replace BI for patients with public drug coverage later the same year. We compared persistence on GI to that on BI in a matched cohort study.

Methods: Patients who started GI between 2013 and 2016 were selected from the Quebec CML registry. Each was matched with a BI user who had recorded use of BI at the same calendar date, had the closest duration of prior BI use and closest age. In both cohorts, patients who previously received therapy other than imatinib for their CML were excluded. Matched pairs were followed until switch in therapy, death, withdrawal of consent or end of study (31 December 2016). Kaplan-Meier curves were constructed to evaluate persistence, defined as time until switch in therapy, between GI and BI users. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for treatment discontinuation or switch with GI, comparing GI with BI, adjusting for sex, obesity, smoking, alcohol consumption, and Charlson comorbidity index.

Results: A total of 167 matched pairs were included; mean age (SD) and mean duration (SD) of prior BI therapy was similar between GI and BI users (57.2 (14.4) and 58.3 (13.4) years and 6.1 (4.2) and 5.7 (4.5), respectively). At 42 months, 72.8% (95% CI, 63.4.5%-81.7%) of GI users and 88.9% (95% CI, 82.8%-93.6%) of BI users persisted with their TKI (Figure= 0.03). Overall, GI use was associated with an increased risk of switch (HR, 2.13; 95% CI, 1.18-3.86), compared with BI. In GI users, 36 patients switched therapy, 11 for suboptimal response (defined as loss of response, including loss of MMR or failure to achieve a milestone) and 25 for intolerance, which included 21 switching back to BI. Most (63.5%) of the switches occurred in the first year of GI use, and most for intolerance (66.7%, n=24). Of note, there were seven grade 3 adverse events in GI users (fatigue, weakness, nausea and vomiting, diarrhea, muscle cramps). Among BI users, 17 patients switched for suboptimal response (n=8), and intolerance (n=9). Of note, in GI and BI users respectively, 13 and 4 patients stopped therapy in deep molecular response.

Discussion: In this matched cohort study with close to 4 years of follow-up, GI users were twice more likely to stop their TKI than users of BI users, marking lower persistence. In most terminations of GI use, the patients reverted to BI, and intolerance was the main cause for TKI switch. Future studies are warranted to investigate the safety profile of GI.

Molecular Responses after Switching from a Standard-Dose Twice-Daily Nilotinib Regimen to a Reduced-Dose Once-Daily Schedule in Patients with Chronic Myeloid Leukemia: A Real Life Observational Study (NILO-RED)

Result Type: Paper
Number: 318
Presenter: Delphine Rea
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Therapy: Treatment Discontinuation, Dose Reduction, and Prognostic Indicators

Delphine Rea, MD1, Jean-Michel Cayuela, PhD2*, Stephanie Dulucq, PhD3* and Gabriel Etienne, MD, PhD4*

1Adult Hematology department, Hôpital Saint-Louis, Paris, France
2Molecular Biology Laboratory, Hôpital Saint-Louis, Paris, France
3Molecular Biology Laboratory, Hôpital Haut Lévèque, Pessac, France
4Hematology Department, Institut Bergonie, Bordeaux, France

 

Introduction: Standard dosing regimen for the BCR-ABL1 tyrosine kinase inhibitor (TKI) nilotinib in chronic myeloid leukemia (CML) is 300mg twice daily (BID) in the frontline setting and 400mg BID in the 2nd line setting or beyond. Patients (pts) are instructed to fast within 2 hours before and 1 hour after medication intake due to significant high-fat food effects on drug bioavailability. On-label dose adjustments to a lower-dose once-daily (QD) regimen are recommended solely in case of significant toxicity.

Study goal: The primary aim of our observational two-center study was to ask whether nilotinib-treated adult CML pts were able to maintain major molecular responses (MMR) within 1 year after conversion to a more convenient nilotinib QD regimen at reduced doses, regardless of reasons for tapering nilotinib. Pts with minor transcripts or a history of blast crisis or allogeneic stem cell transplantation were excluded.

Patients: Eighty one pts in chronic phase were identified and included and results from the first 67 pts with a follow-up of at least 12 months after the switch to the once-daily dose-reduced nilotinib regimen are presented. Median age at study entry was 52 years (range: 19-82). There were 25 males (37.3%) and the Sokal score was low, intermediate, high or unknown in 43.3%, 37.3%, 13.4% and 6% of pts, respectively. All pts had major-type BCR-ABL1 transcripts. Nilotinib was started as 1st line TKI at 300mg BID in 68.6% of pts and as 2nd or subsequent line TKI at 400 or 300 mg BID in 31.4% of pts due to intolerance, warning, resistance or absence of a deep molecular response on prior therapy. Median duration of nilotinib prior switching to a reduced QD dosing was 29 months (range: 1-94) and median duration of MMR was 25 months (range: 3-212). Primary reason for the switch to a reduced QD nilotinib dosing was non-serious adverse events in 37.3% of pts and improvement in pts convenience in 62.7% of pts. Nilotinib was reduced down to 450mg QD, 400mg QD or 300mg QD in 86.6%, 10.4% and 3% of pts, respectively. A 2nd dose reduction from 450mg to 300mg QD was performed in 30 pts after a median time of 18 months (range: 4-37). The median duration of low-dose nilotinib QD was 24 months (5-54). No severe tolerance issues were encountered and no ischemic cardiovascular events occurred. Eleven pts stopped nilotinib due to treatment-free remission attempt (n=10) or persistent adverse event (n=1). All pts were alive at last follow-up.

Evolution of molecular responses

At baseline, the number of pts in MMR, MR4 and ≥MR4.5 was 9 (13.4%), 17 (25.4%) and 41 (61.2%), respectively and 32 pts (47.8%) had undetectable BCR-ABL1 transcripts. Median BCR-ABL1/ABL1 % IS was 0.006% (range: 0.0007-0.063) and median ABL1 copy number in pts with undetectable transcripts was 87259 (range: 36018-921339). Only 2 pts treated with 1st line nilotinib lost MMR 4 and 6 months after QD dose reduction of nilotinib with BCR-ABL1/ABL1 % IS at 0.13 and 0.11%, respectively. Both pts spontaneously regained MMR 4 months later without any treatment modification. Kaplan-Meier analysis of survival without unconfirmed MMR loss was 97% (95% CI: 92.9-100) at 12 months and analysis by molecular response category showed that none of the pts who were at least in MR4 at baseline lost MMR (Figure 1). At last follow-up on low-dose QD nilotinib, the number of pts in MMR, MR4 and ≥MR4.5 was 4 (6.3%), 11 (16.4%) and 52 (77.6%), respectively and 37 pts had undetectable transcripts (55.2%). Median BCR-ABL1/ABL1 % IS was 0.0035% (range: 0.00025-0.058) and median ABL1 copy number in pts with undetectable transcripts was 96000 (range: 23285-472000).

Ten pts in long-lasting deep molecular response stopped nilotinib without further treatment after a median duration of TKI and of nilotinib of 60 months (range: 50-149) and 56 months (range: 42-87), respectively. Their follow-up after nilotinib discontinuation was 18 months (range: 5-33). Only 1 of them lost MMR and restarted therapy 5 months later while the others remained treatment-free.

Conclusion: Switching to a nilotinib QD regimen at reduced doses as maintenance therapy after achievement of a MMR on standard-dose nilotinib BID schedule is feasible and safe in chronic phase CML pts regardless of prior treatment history and does not compromise the anti-leukemic efficacy of nilotinib. Our results may pave the way for clinical trials aiming at systematic avoidance of overtreatment and improvement of pts convenience in treatment with nilotinib.

Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Result Type: Paper
Number: 896
Presenter: Carlo Gambacorti-Passerini
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Therapy: Results of Clinical Trials

Carlo Gambacorti-Passerini, MD1, Michael W. Deininger, MD, PhD2, Michael J. Mauro, MD3, Charles Chuah, MD4, Dong-Wook Kim, MD, PhD5, Iryna Dyagil, MD PhD6*, Natalia Glushko7*, Dragana Milojkovic, MBBS, PhD8*, Philipp D. le Coutre, MD9, Valentín García Gutiérrez, PhD10, Rocco J. Crescenzo, DO, FACOI11*, Eric Leip, PhD12*, Nathalie Bardy-Bouxin, PhD13*, Andreas Hochhaus, MD14, Timothy H. Brümmendorf15 and Jorge E. Cortes, MD16

1University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
2University of Utah, Salt Lake City, UT
3Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York, NY
4Singapore General Hospital, Duke-NUS Medical School, Singapore, Singapore
5Seoul St. Mary’s Hospital, Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea, Republic of (South)
6Hematology, National Research Center For Radiation Medicine, Kiev, UKR
7Ivano-Frankivsk Regional Clinical Hospital, Ivan0-Frankivsk, Ukraine
8Department of Haematology, Hammersmith Hospital, Imperial College, London, United Kingdom
9Charité-Universitätsmedizin Berlin, Berlin, Germany
10Hematology Department, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
11Pfizer, Collegeville, PA
12Pfizer, Cambridge, MA
13Global Research and Development, Pfizer International Operation-Oncology, Paris, France
14Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
15Universitätsklinikum RWTH Aachen, Aachen, Germany
16Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX

 

 

Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up.

Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph– patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted.

Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P<0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P<0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure).

Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively.

Conclusion: After 18 months of follow-up, the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML.