Drs. Enright and McGlave succinctly review the biology of chronic myelogenous leukemia (CML) and highlight the therapeutic role of allogeneic stem-cell transplantation. Two points, however, warrant further discussion.The first is that a regimen containing interferon-alfa (Intron A, Roferon-A) is optimal front-line therapy for the great majority of CML patients.[1] The second is that use of an interferon-alfa-based regimen prior to allogeneic stem-cell transplantation does not adversely affect post-transplant mortality, morbidity, or anti-CML efficacy.

Interferon-Alfa-Based Regimens Are Optimal Front-Line Therapy

Of 274 patients treated with interferon-alfa-based regimens at The M.D. Anderson Cancer Center, 80% achieved complete hematologic remission (CHR), and 58% had a cytogenetic response (complete in 26%, major in 38%)[1] The median survival was 89 months (confidence interval, 66 to 102 months). Achieving a cytogenetic response after 12 months of therapy was associated with a statistically longer survival by landmark analysis—5-year survival rates dated from 12 months into therapy were 90% for complete cytogenetic response, 88% for partial cytogenetic response, 76% for minor cytogenetic response, and 38% for other response categories.

A multivariate analysis incorporating major cytogenetic response as a time-dependent variable showed it to be an independent prognostic factor for survival; patients achieving a major cytogenetic response had a 0.21 risk of death per unit time, compared with the total study group. Confirming this finding is the observation of the favorable impact of cytogenetic response within prognostic risk groups by landmark analysis. Survival improvement is due to a delay in progression to the blastic phase and is independent of pretreatment characteristics. Studies from many single institutions and cooperative groups have confirmed the efficacy of interferon-alfa in CML.[2]

Recently, four randomized trials comparing interferon-alfa with conventional chemotherapy have been reported.[3-6] Table 1 summarizes the results of large interferon-alfa studies in terms of study design, patient number, intended and delivered interferon-alfa dose, CHR and cytogenetic response profiles, and survival results.[1,3-10] In three of the prospective, randomized studies, interferon-alfa therapy prolonged survival and delayed progression to the blastic phase when compared with conventional therapy.[3,5,6] In all four randomized trials, interferon-alfa therapy produced a higher rate of major and complete cytogenetic response than did conventional chemotherapy.

Cytogenetic response to interferon-alfa was generally correlated with survival, and both studies that failed to show this prognostic association had a low rate of major cytogenetic responses, possibly because of low actual doses of interferon-alfa administered.[4,9] Two other studies showing a correlation between cytogenetic response and survival also reported that patients treated with interferon-alfa who did not achieve a cytogenetic response had survivals equivalent to patients receiving conventional chemotherapy.[5,11] The Medical Research Council study showed a longer survival duration for patientswho received interferon-alfa even if they did not achieve a cytogenetic response, but those who achieved a cytogenetic response lived longer than those who did not.[3]

Complete hemotologic response rates in similar study populations (ie, early chronic-phase CML) have ranged from 31% to 80%.[2-11] Some variability in the CHR rates may be due to
different response criteria or protocol treatment designs. This would not explain the large differences in the cytogenetic (18% to 58%), major cytogenetic (10% to 38%), and complete cytogenetic response (6% to 26%) rates. Differences in cytogenetic response results may be due to: (1) different risk group distributions; (2) patient and physician motivation; (3) the actual dose of interferon-alfa delivered; (4) the frequency of cytogenetic studies; (5) inclusion of advanced- or accelerated- phase patients, and (6) use of interferon-alfa monotherapy as induction, with consequent higher early dropout rates. When patients were analyzed for response to interferon-alfa and survival within risk groups, the data still showed an interferon-alfa-associated advantage in each risk group, suggesting that the dose-intensity of interferon-alfa increased the quality of cytogenetic response and prolonged survival.

Initial studies of interferon-alfa plus cytotoxic agents were conducted to determine whether patients who failed to achieve a CHR or cytogenetic remission on interferon-alfa alone might do so with combined therapy, and whether cytogenetic remission rates might improve with the increased myelosuppression associated with combination therapy. Combinations of interferon-alfa with hydroxyurea (Hydrea) and with cytarabine (ara-C) were initially investigated in patients with late chronic-phase disease. Data from a United Kingdom group and The M.D. Anderson Cancer Center indicated that both interferon-alfa/hydroxyurea and interferon-alfa/ara-C seemed to prolong late chronic phase, in contrast to treatment with interferon-alfa or the cytotoxics alone.[12,13] Subsequent studies indicated that interferon-alfa/cytotoxic combinations may be the optimal current therapy for patients with early chronic- phase disease (Table 2).[10,14-17]

In human malignancies, achieving a minimal tumor burden is a prerequisite for cure or for improvement of survival. The causal association between Philadelphia chromosome (Ph)-related molecular events and the development of CML suggests that a reduction in Ph-positive cells should be accepted as indicative of a reduced CML tumor burden. Reduction in tumor burden, as reflected by CHR, has been associated with significant survival prolongation in all studies in which it has been examined.[3,5,6,8]

Achieving a minimal cytogenetic tumor burden has also been associated with a significant survival advantage by landmark and/or multivariate analysis in the majority of studies to date. Thus, most current data suggest that achieving a minimal CML tumor burden, as reflected by hematologic and cytogenetic remissions, will have a favorable impact on outcome, and should be pursued as a therapeutic objective in future investigations.

Prior IFN-A Therapy Does Not Adversely Affect Allogeneic Stem-Cell Transplantation

Busulfan (Myleran) therapy prior to allogeneic stem-cell transplantation has been shown to have an adverse impact on post-transplant survival.[18] This is not the case with inteferon-alfa therapy prior to transplant. Data from Beelen et al suggesting that interferon-alfa therapy prior to allogeneic stem-cell transplantation might compromise outcome have not been reproduced in three other larger patient cohorts.[19,20-22] An analysis of data from the International Bone Marrow Transplant Registry (IBMTR) on 882 CML patients who had been treated with allogeneic stem-cell transplantation showed that interferon-alfa therapy prior to transplantation had no adverse impact on outcome.[21] Patients with a matched sibling donor available for allogeneic stem-cell transplantation may benefit from this strategy as first-line therapy, depending on individual center transplantation results.

Summary

Allogeneic stem-cell transplantation and interferon-alfa-based therapy have undoubtedly changed the natural history of CML. Despite these advances, most CML patients still die from the disease. Many patients do not qualify for an allogeneic stem-cell transplant, either because of age or lack of an appropriate donor, and only a fraction of patients achieve a complete cytogenetic response with interferon-alfa-based therapy. Prior treatment with interferon-alfa does not adversely affect allogeneic stem-cell transplantation outcome.

The optimal choice of therapy for CML patients depends on patient age, disease stage, availability of a HLA-compatible donor, patient preference, and tolerance of interferon-alfa therapy. The combination of interferon-alfa and ara-C is superior to interferon-alfa alone, and continuous administration of ara-C may be more effective than intermittent administration when the two drugs are combined[15].

Further understanding of the molecular biology of CML and of the molecular basis for the anti-CML effect of interferon-alfa should help guide the search for curative therapy.