Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia.
OBJECTIVE
Imatinib induces sustained remissions in patients with chronic myelogenous leukemia (CML), but fails to eradicate CML stem cells. This is of major concern regarding the issues of cure, long-term imatinib tolerability, and imatinib resistance. We therefore asked whether interferon alfa-2a (IFN) alone could maintain molecular remissions achieved by a prior combination therapy with imatinib and IFN.


METHODS
Imatinib therapy was stopped in 20 patients who had concomitantly been pretreated with imatinib and IFN for a median of 2.4 years (range, 0.2 to 4.8 years) and 2.5 years (range, 0.2 to 4.9 years), respectively. After imatinib discontinuation, remission status was monitored monthly by quantitative analysis of the peripheral-blood BCR-ABL mRNA levels using real-time polymerase chain reaction. Proteinase-3 expression and proteinase-3-specific cytotoxic T cells (CTLs) were longitudinally measured to assess putative markers of IFN response.


RESULTS
With a median time of 2.4 years after imatinib withdrawal (range, 0.5 to 4.0 years), 15 (75%) of 20 patients remained in remission. The number of patients in complete molecular remission increased under IFN from two patients at baseline to five patients after 2 years. Relapses occurred in five patients within 0.4 years (range, 0.2 to 0.8 years), but patients underwent rescue treatment with imatinib, re-establishing molecular remission. IFN therapy was associated with an increase in the expression of leukemia-associated antigen proteinase 3 and induction of proteinase-3-specific CTLs.


CONCLUSIONS
Treatment with IFN enables discontinuation of imatinib in most patients after prior imatinib/IFN combination therapy and may result in improved molecular response. Induction of a proteinase-3-specific CTL response by IFN may contribute to this effect.
Klinik für Hämatologie, Onkologie und Immunologie, Philipps Universität Marburg und Universitätsklinikum Giessen und Marburg, Standort Marburg, Marburg, Germany.
Andreas
A
Burchert
Martin C
MC
Müller
Philippe
P
Kostrewa
Philipp
P
Erben
Tilman
T
Bostel
Simone
S
Liebler
Rüdiger
R
Hehlmann
Andreas
A
Neubauer
Andreas
A
Hochhaus
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001549:Benzamides; D015415:Biomarkers / Q000097:blood; D018572:Disease-Free Survival; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000097:blood / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D016131:Lymphocyte Subsets / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin / Q000097:blood; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011994:Recombinant Proteins; D055502:Secondary Prevention; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D053146:Myeloblastin