Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients.
Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.
Affiliations of authors: Department of Health Sciences, University Milano Bicocca, Monza, Italy (CGP, FF, AS, SR, MC, LMo, CM, LA, RP); Hematology Unit (CGP) and Nuclear Medicine and PET Unit (CM, LG), San Gerardo Hospital, Monza, Italy; M Tettamanti Research Center, Pediatric Clinic University of Milano Bicocca, Monza, Italy (GG); Medical Genetics Laboratory, San Gerardo Hospital, Monza, Italy (ES); Istituto di Ricerca Pediatrico Fondazione Città della Speranza, Pediatric Clinic University of Padova, Padova, Italy (LMu); H.-Hartziekenhuis Roeselare-Menen vzw, Roeselare, Belgium (DD); Trillium Health Centre, Mississauga Site, Mississauga ON, Canada (MHK); Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria (MS); Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany (RO); Hematology Institute, Beilinson Hospital, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (AMC); Department of Haematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany (MG); Hematology/Stem Cell Transplantation, Maisonneuve Rosemont/University of Montreal, Montreal, QC, Canada (LB); School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland (GC).
Carlo
C
Gambacorti Passerini
Francesca
F
Farina
Alessandra
A
Stasia
Sara
S
Redaelli
Monica
M
Ceccon
Luca
L
Mologni
Cristina
C
Messa
Luca
L
Guerra
Giovanni
G
Giudici
Elena
E
Sala
Lara
L
Mussolin
Dries
D
Deeren
Michael H
MH
King
Michael
M
Steurer
Rainer
R
Ordemann
Amos M
AM
Cohen
Matthias
M
Grube
Lea
L
Bernard
Gianpaolo
G
Chiriano
Laura
L
Antolini
Rocco
R
Piazza
D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077547:Crizotinib; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000032:analysis* / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000187:drug effects; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases