Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing.
Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304.
Klion
Amy D
AD
Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA. aklion@nih.gov
Robyn
Jamie
J
Maric
Irina
I
Fu
Weiming
W
Schmid
Laura
L
Lemery
Steven
S
Noel
Pierre
P
Law
Melissa A
MA
Hartsell
Marilyn
M
Talar-Williams
Cheryl
C
Fay
Michael P
MP
Dunbar
Cynthia E
CE
Nutman
Thomas B
TB
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001549:Benzamides; D054316:Biomarkers, Pharmacological / Q000032:analysis; D001706:Biopsy; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000068877:Imatinib Mesylate; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics*; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics*; D012008:Recurrence; D012074:Remission Induction; D028761:Withholding Treatment; D039221:mRNA Cleavage and Polyadenylation Factors / Q000032:analysis / Q000235:genetics*
D000970:Antineoplastic Agents; D001549:Benzamides; D054316:Biomarkers, Pharmacological; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha
Blood. 2002 May 15;99(10):3792-800
11986238
N Engl J Med. 2003 Mar 27;348(13):1201-14
12660384
Blood. 2003 Jun 15;101(12):4701-7
12576334
N Engl J Med. 2003 Oct 9;349(15):1423-32
14534335
Haematologica. 2003 Oct;88(10):1117-22
14555307
Blood. 2004 Jan 15;103(2):473-8
14504092
Leuk Res. 2004 May;28 Suppl 1:S71-3
15036945
Blood. 2004 Oct 1;104(7):2204-5
15377577
Blood. 2005 Mar 1;105(5):2093-8
15345592
Haematologica. 2005 Jul;90(7):979-81
15996937
Br J Haematol. 2006 Feb;132(3):286-92
16409293
Leuk Res. 2006 Aug;30(8):965-70
16406016
N Engl J Med. 2006 Dec 7;355(23):2408-17
17151364
Jpn J Clin Oncol. 2006 Nov;36(11):704-11
17068083
Blood. 2007 Jan 1;109(1):58-60
16973963
Leukemia. 2007 Mar;21(3):489-93
17252009
Blood. 2007 Jun 1;109(11):4635-40
17299092
Hematology Am Soc Hematol Educ Program. 2001;:87-112
11722980
Blood. 2002 Jan 1;99(1):319-25
11756187
N Engl J Med. 2002 Feb 28;346(9):645-52
11870241