Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.
Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.
Hemato-Oncology Unit, Centre Hospitalier de Versailles, Le Chesnay, France; Université Versailles Saint Quentin en Yvelines, EA4340, Université Paris-Saclay, Communauté Paris-Saclay, France;
Philippe
0000-0003-3238-4494
P
Rousselot
Laboratory of Hematology, University Hospital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; EA3518, University Paris Diderot, Paris, France;
Marie Magdelaine
MM
Coudé
Medicine Department II, Johann Wolfgang Goethe Universität, Frankfurt, Germany;
Nicola
N
Gokbuget
Department of Internal Medicine/Experimental Oncology, University of Milano Bicocca, Monza, Italy;
Carlo
C
Gambacorti Passerini
Division of Hematology, Hospices Civils de Lyon, INSERM U1052-Centre National de la Recherche Scientifique UMR 5286, Centre Hospitalier Lyon Sud, Pierre Bénite, France;
Sandrine
S
Hayette
Laboratory of Hematology, University Hospital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; EA3518, University Paris Diderot, Paris, France;
Jean-Michel
JM
Cayuela
Division of Hematology, Institut Universitaire de Cancérologie, Toulouse, France;
Françoise
F
Huguet
Division of Hematology, Hôpital du Haut-Levêque, Pessac, France;
Thibaut
T
Leguay
Hematology Department, CHU Hotel-Dieu, Nantes, France;
Patrice
P
Chevallier
Division of Hematology, Centre Hospitalier Sud Francilien, Corbeil Essonne, France;
Celia
C
Salanoubat
Division of Hematology, Hôpital de Brabois, Centre Hospitalier Universitaire de Nancy, Nancy, France;
Caroline
C
Bonmati
Service d'Oncologie et d'Hématologie, Hôpital de la Source, Orléans, France;
Magda
M
Alexis
Division of Hematology, Centre Hospitalier Universitaire d'Angers, Angers, France; INSERM U892/Centre National de la Recherche Scientifique 6299, Angers, France;
Mathilde
M
Hunault
Division of Hematology, Institut Curie-Hôpital Rene Huguenin, Saint-Cloud, France;
Sylvie
S
Glaisner
Division of Hematology, Centre Hospitalier Départemental Felix Guyon, Saint Denis, La Réunion, France;
Philippe
P
Agape
Division of Hematology, Centre Hospitalier Universitaire de Brest, Brest, France;
Christian
C
Berthou
Division of Hematology, Centre Hospitalier Universitaire de Nîmes, Nîmes, France;
Eric
E
Jourdan
Division of Hematology, Hotel Dieu, Valenciennes, France;
José
J
Fernandes
Division of Hematology, Centre Hospitalier Victor Dupouy, Argenteuil, France;
Laurent
L
Sutton
Division of Hematology, Centre Hospitalier de la Côte Basque, Bayonne, France;
Anne
A
Banos
Division of Hematology, Centre Hospitalier Universitaire, Caen, France;
Oumedaly
O
Reman
Division of Hematology, Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France;
Bruno
B
Lioure
Division of Hematology, Hospices Civils de Lyon, INSERM U1052-Centre National de la Recherche Scientifique UMR 5286, Centre Hospitalier Lyon Sud, Pierre Bénite, France;
Xavier
X
Thomas
Division of Hematology, Centre Hospitalier Universitaire d'Angers, Angers, France; INSERM U892/Centre National de la Recherche Scientifique 6299, Angers, France;
Norbert
N
Ifrah
Laboratoire de Cytogénétique Onco-Hématologique, CHU Timone Enfants, Aix-Marseille University, Marseille, France;
Marina
M
Lafage-Pochitaloff
Service de Gériatrie Aigue Polyvalente and.
Anne
A
Bornand
Délégation à la Recherche Clinique et à l'Innovation, Hôpital Mignot, Le Chesnay, France;
Laure
L
Morisset
Division of Hematology, CHR Mons-Hainaut, Mons, Belgium;
Valérie
V
Robin
Department of Molecular Biology, Johann Wolfgang Goethe University, Frankfurt, Germany;
Heike
H
Pfeifer
Département d'Hématologie, d'Oncologie Médicale et de Radiothérapie Oncologique, Centre Hospitalier de Jolimont-Lobbes, Haine Saint Paul, Belgium;
Andre
A
Delannoy
Department of Clinical Hematology, ICO-Hospital Germans Trias i Pujol, Jose Carreras Research Institute, Badalona, Spain;
Josep
J
Ribera
Azienda ULSS 12 "Veneziana" Direttore U.O.C. Ematologia, Venezia, Italy;
Renato
R
Bassan
Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France;
Marc
M
Delord
Department of Hematology, Johann Wolfgang Goethe University, Frankfurt, Germany;
Dieter
D
Hoelzer
Division of Hematology, Hôpital Saint-Louis, AP-HP, University Paris Diderot, Paris, France; and.
Herve
H
Dombret
Institute of Cancer & Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.
Oliver G
0000-0001-9559-1330
OG
Ottmann
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069439:Dasatinib / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010677:Philadelphia Chromosome / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib