36 48 60 72 84 96 108 120 Months

Figure 7.4 Survival probabilities in patients with intermediate-risk cytogenetics [normal, +8, del11q, and miscellaneous abnormalities not including -5/-7, inv(16), or t( 8;21)] according to de novo versus secondary distinction

Figure 7.5 Survival probabilities in patients with chromosome 5 and/or 7 abnormalities according to de novo versus secondary distinction

International Working Group (IWG) sponsored by the National Cancer Institute (NCI) to publish criteria for response in MDS, intended with trials of LI in mind, which recognize various categories of MR.37 Such MRs are also being noted in studies of LI in AML.28-31 However, as noted by the authors of the IWG report, "it will be important to apply these guidelines prospectively and to critically assess their validity and usefulness."

This statement assumes particular significance given our comparison of the effects on survival of achieving CR versus achieving MR with HI.38 At M.D. Anderson, we stratified 314 patients with high-risk MDS or AML who survived HI but failed to achieve CR according to whether they exhibited MR on the date they were removed from study. We considered MRs as marrow CR, or as CR with incomplete platelet recovery (CRP) (with less than 5% marrow blasts, normal neutrophil count, and platelet transfusion independence). We then compared survival time in patients according to whether they achieved (1) marrow CR, (2) CRP, (3) CR as usually defined (CRP and a platelet count >100,000), or (4) none of the above. Survival was dated from date of CR or from date the patient was removed from study. Results are shown in Figure 7.6. Although patients who achieved an MR (marrow CR, CRP) may have done better than patients who did not, the most striking difference was between patients who achieved CR and those who did not.

Findings were similar in patients with high-risk MDS and in those with AML. The results did not reflect differences in time to CR versus time to resistance date or between the times to resistance date in the various subsets of resistant patients. Thus, the observations suggest that only CR potentially lengthens survival in these diseases after administration of HI. This observation is perhaps not surprising. In particular, if many CRs are transient and thus contribute little to an increase in survival time, it may be unrealistic to expect responses, such as MRs, which are qualitatively inferior to CR, to be associated with a survival benefit. Whether MR will have less effect than that of CR in increasing survival when patients are given LI rather than HI is unknown. However, the data in Figure 7.6 have two consequences. First, they provide an ethical basis for administering either HI or LI as the initial investigational therapy to older patients with secondary AML/MDS. Specifically, the figure suggests that if the beneficial effect of LIs on TRM is accompanied by a lower CR rate, LI and HI may have equivalent effects on survival. Second, the data emphasize the importance of assessing the relationship between survival and the various categories of MR. Such assessment is facilitated by the short survival of patients of age 60 and above with secondary AML/MDS.

The discussion to date has focused on survival as the principal outcome of interest. However, although they may not improve survival time in older patients with secondary AML/MDS, a major advantage of LIs is the possibility that they will provide better "quality of life" (QOL) than do HIs. Thus, unlike HIs, LIs are often administered by mouth and, in principle, require less time in hospital.39 However, if HI is more likely to produce a CR than LI, and if achievement of CR is necessary to lower the risk of infection and hemorrhage that are frequent contributors to morbidity in older patients with AML/MDS, HI may be more likely to improve QOL than LI. The above discussion stresses the need for reproducible QOL measurements in patients receiving investigational HI or LI.

A third type of investigational approach in older patients with secondary AML/MDS involves nonablative allogeneic transplant (minitransplant). Minitransplantation relies essentially entirely on a graft-versus-leukemia effect; the purpose of the attenuated doses of chemotherapy used as the preparative regimen is to allow the donor cells to engraft. The source of stem cells is often the blood rather than the bone marrow.40-42

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