Low doses of interferon-alpha are as effective as higher doses in inducing remissions and prolonging survival in chronic myeloid leukemia.

OBJECTIVE: To determine the toxicity and efficacy of low-dose interferon-alpha therapy in inducing remissions and prolonging survival in patients with chronic myeloid leukemia. DESIGN: Phase II evaluation and comparison with historical control patients and other series in which the investigators used higher interferon-alpha doses. SETTING: Tertiary care leukemia research clinic. PATIENTS: 41 patients with newly diagnosed or previously treated chronic-phase, Philadelphia chromosome-positive chronic myeloid leukemia received interferon-alpha at a dose of 2 x 10(6) U/m2 body surface area daily for 28 days and then three times weekly. MEASUREMENTS: Complete blood counts and physical examinations were done monthly to determine hematologic remission and toxicity. To determine karyotypic response, bone marrow cytogenetic analyses were done at 6 monthly intervals in patients who achieved a complete hematologic remission. In addition, Kaplan-Meier survival curves and median survival values were generated from diagnosis and the start of therapy with interferon-alpha. RESULTS: 70% of patients treated with low-dose interferon-alpha within 1 year of diagnosis achieved a complete hematologic remission, and 22% of these patients had a major or complete karyotypic response. Investigators who used higher interferon-alpha doses in similar patient populations have reported complete hematologic remission rates of 59% to 70% and major and complete cytogenetic response rates of 16% to 29%. The Kaplan-Meier estimated 5-year survival rate of minimally pretreated patients in our study is 73% (95% CI, 51% to 95%), which compares favorably with survivals reported by investigators who used higher doses. The estimated yearly cost of the interferon-alpha used in our study is $5953 compared with a median of $24,375 for the higher doses used by other investigators. Less toxicity was also observed. CONCLUSION: Low-dose interferon-alpha is as effective as higher-dose interferon-alpha in inducing remissions and prolonging survival in patients with chronic myeloid leukemia but is considerably less expensive and toxic.

T-cell immunity to the joining region of p210BCR-ABL protein.

The hallmark of chronic myelogenous leukemia is the translocation of the human c-abl protooncogene (ABL) from chromosome 9 to the specific breakpoint cluster region (bcr) of the BCR gene on chromosome 22. The t(9;22)(q34;q11) translocation results in the formation of a BCR-ABL fusion gene that encodes a 210-kDa chimeric protein with abnormal tyrosine kinase activity. The ABL and BCR genes are expressed by normal cells and thus the encoded proteins are presumably nonimmunogenic. However, the joining-region segment of the p210BCR-ABL chimeric protein is composed of unique sequences of ABL amino acids joined to BCR amino acids that are expressed only by malignant cells. The current study demonstrates that the joining region of BCR-ABL protein is immunogenic to murine T cells. Immunization of mice with synthetic peptides corresponding to the joining region elicited peptide-specific, CD4+, class II major histocompatibility complex-restricted T cells. The BCR-ABL peptide-specific T cells recognized only the combined sequence of BCR-ABL amino acids and not BCR or ABL amino acid sequences alone. Importantly, the BCR-ABL peptide-specific T cells could recognize and proliferate in response to p210BCR-ABL protein. The response of peptide-specific T cells to protein demonstrated that p210BCR-ABL can be processed by antigen-presenting cells so that the joining segment is bound to class II major histocompatibility complex molecules in a configuration similar to that of the immunizing peptide and in a concentration high enough to stimulate the antigen-specific T-cell receptor. Thus, BCR-ABL protein represents a potential tumor-specific antigen related to the transforming event and shared by many individuals with chronic myelogenous leukemia.