Determining the Durability of Interferon-Induced Complete Cytogenetic Responses in CML
February 1, 2000 4 minutes read
Determining the Durability of Interferon-Induced Complete Cytogenetic Responses in CML
ABSTRACT & COMMENTARY
Synopsis: Interferon treatment results in complete hematologic remission in approximately 75% of CMl patients and about one-half of these will also have the disappearance of the Ph1 chromosome (cytogenetic remission). The question of whether cytogenetic remission reflects a complete disappearance of the leukemic clone (cure) has, until recently, been unclear. Leukemic cells persist at a level detected by PCR and quantitative data would suggest that the lower the level, the more durable the remission. Accordingly, interferon treatment should continue beyond the point of cytogenetic remission.
Source: Hochhaus A, et al. Blood 2000;95:62-66.
Currently, interferon a is considered by many to be the initial treatment of choice for patients with chronic myelogenous leukemia (CML), primarily based upon its superior rate of inducing complete cytogenetic remission compared to alternative treatments such as hydroxyurea or busulfan.1 However, it remains unclear whether some patients in remission are actually cured, or for how long interferon therapy should be continued.
These are two of the questions addressed by the published cooperative effort from the German and UK CML Study Groups. Hochhaus and colleagues obtained sequential blood samples from 54 patients who had achieved complete cytogenetic remission (CR) with interferon therapy and performed reverse transcriptase-polymerase chain reaction (RT-PCR) to quantitatively assess the persistence of the leukemic clone.
Typically, the disappearance of the Ph1 chromosome by cytogenetic analysis is used as an indicator of clinical remission in CML.2 However, this assessment has a maximum sensitivity of only 10-2. In contrast, the RT-PCR can detect a single cell with the hallmark BCR-ABL translocation in a population of 106 cells.3 Thus, RT-PCR is at least four orders of magnitude more sensitive than cytogenetic analysis. In the current study, total ABL (normal) transcripts were quantitated for internal control and results were expressed as the ratio BCR-ABL/ABL.
Of the 54 patients in complete cytogenetic remission, sequential samples were examined over a median duration of 1.9 years (range, 0.3-11 years). All 54 patients had molecular evidence of residual disease, although three patients were transiently negative by RT-PCR. The median BCR-ABL/ABL ratio at the time of maximal response (i.e., the lowest level for the patient) was 0.045%.
During the study, 14 of the 54 patients relapsed, 11 cytogenetically to chronic phase disease and three directly to blast phase. The median ratio of BCR-ABL/ABL at maximal response was significantly higher in patients who relapsed than in those who remained in CR (0.49% vs 0.021%, P < 0.0001).
These findings indicate that the level of residual disease falls with time in complete responders to IFN, but molecular evidence of disease is rarely, if ever, eliminated. The actual level of minimal residual disease correlates with the probability of relapse. On the basis of these findings, Hochhaus et al suggest that, for patients who reach CR, IFN should be continued to maintain the level of leukemic cells below the threshold for detection by cytogenetic analysis.
COMMENT by William B. Ershler, MD
This paper is an excellent example of the translation of new and innovative molecular technology to important clinical questions. Using PCR to amplify key DNA sequences (BCR-ABL), we now know that cytogenetic remissions are not necessarily cures. In fact, they are unlikely to be so in the great majority of cases. Quantitative data (by RT-PCR) supports the conventional wisdom that the lower the tumor burden (i.e., the lower the BCR-ABL/ABL ratio) the more likely the clinical remission will persist. Although PCR is now used commonly in clinical laboratories, this type of quantitative assessment is not. Although technically more difficult, it would be a useful addition for the management of CML patients.
Sequential samples from the same individual were found to have continuing response to IFN therapy below the cytogenetic threshold. Thus, the issue of how long to continue with therapy remains unresolved. It would seem reasonable to suggest that patients in cytogenetic remission remain on IFN as long as tolerable, or until signs of disease progression are observed. It might also be reasonable to suggest that patients remain on IFN until there has been a plateau in the measured tumor burden. At that time, an innovative approach, using, for example, a new agent or marrow transplantation might be worthwhile. This would be the type of question best resolved by clinical trial within or between the cooperative oncology groups.
References
1. Kantarjian HM, et al. Ann Intern Med 1995;122:254-261.
2. Lee MS, et al. Blood 1992;79:1920-1923.
3. Kurzrock R, et al. J Clin Oncol 1998;16:1526-1531.
Which of the following statements about interferon treatment for chronic myelogenous leukemia is most accurate:
a. Disappearance of the Ph1 chromosome occurs in approximately 75% of cases and in 40% the leukemic clone has been eradicated and cure is likely.
b. Hematologic remission occurs in approximately 75%; disappearance of the Ph1 chromosome (cytogenetic remission) occurs in approximately one-half of those in hematologic remission; and PCR indicates that the great majority of those in cytogenetic remission have detectable genetic translocation (BCR-ABL) indicating persistent disease.
c. Hematologic remission occurs in approximately 75%; disappearance of the Ph1 chromosome (cytogenetic remission) occurs in approximately one-half of those in hematologic remission; and PCR indicates that the great majority of those in cytogenetic remission have no detectable genetic translocation (BCR-ABL) indicating persistent likely cure.
d. PCR indicates that the majority of those patients with cytogenetic remission have developed new translocations that are thought to stabilize the leukemic clone and prolong remission.
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