Allogeneic stem cell transplantation

Only two studies report results obtained with allogeneic SCT in adult patients with CMML.46 47 The outcome of such patients was traditionally included in studies of allogeneic SCT in patients with MDS, of which CMML has been considered a subcategory. Recent WHO classification established CMML as a separate category1; the effect of the reclassification on the prognostic impact of SCT is not yet appreciated.

In a European study,46 50 patients with CMML underwent SCT at 43 centers; 44 of the donors were HLA matched (38 siblings, six unrelated donors, and one nonsibling relative), and six were partially mismatched. At a median age of 44 years (range 19-63 years), this patient group was clearly selected with respect to age; 40% had karyotypic abnormalities and 36% had between 5 and 29% marrow blasts at the time of transplantation. The median time from diagnosis to SCT was 9 months. Two patients (4%) failed to engraft, and the treatment-associated mortality was high (47%). Median follow-up was 29 months (range 1-59 months); the 5-year estimated overall survival rate was 21%, the disease-free survival rate 16%, and the 5-year estimated probability of relapse 61%.46 No significant associations with outcome were identified, although transplantation early in the disease might have had a positive influence.46 The probability of relapse was higher in patients without graft-versus-host disease

(51%) than in those with this disease (29%), and the probability of relapse was higher in patients who received T-cell-depleted grafts (61%) than in those who did not (45 %), suggesting a favorable graft-versus-leukemia effect.

Another study47 reported results for 21 patients with de novo CMML (12 with "proliferative" disease and nine with nonproliferative disease) who underwent SCT. The cohort consisted of both adults and children (median age 47 years). Twelve of the donors were HLA-identical siblings, four were matched unrelated donors, and five were mismatched donors. Before SCT, only two patients had received intensive combination chemotherapy after progression to AML. After SCT, five patients died of organ failure, two died of chronic graft-versus-host disease, and five relapsed and died. The cumulative relapse rate at 3 years was 25%, and 0.7-8.1 years after transplantation (median 6.9 years), nine (43%) of the patients were still alive.47 The small size of the patient cohort limited the significance of covari-ates associated with outcome. SCT later in the course of disease and signs of disease acceleration (e.g., more than 5% marrow blasts), but not abnormal karyotype or proliferative disease, appeared to influence the outcome negatively: four of the five patients who relapsed had an increased percentage of marrow blasts at the time of transplantation.

Finally, a European study of SCT in 43 patients with childhood CMML48 revealed a 5-year event-free survival rate of 31% (38% in patients who received cells from HLA-matched siblings). However, the relapse rate of 58% suggested resistant disease. The major obstacles of the few studies that have examined the effect of SCT on patients with CMML were the toxicity of the procedure and resistant disease. Additional results, including those for a few CMML patients in reports on MDS, are scattered in the literature, and no critical review is currently available. References to some recent studies are found in a review on the role of SCT in MDS49 and MPD.50-52 The conclusion that can be drawn is that SCT is feasible and occasionally "curative" only in younger patients, even though the procedure is associated with considerable morbidity and mortality, and young people make up a small proportion of patients with CMML. This interpretation is compromised by the small number of study patients to date and the heterogeneity of CMML.

Newer transplantation approaches attempt to avoid the excessive toxicity of current conditioning regimens by using lower doses of immunosuppressive drugs (e.g., fludarabine or antithymocyte globulin) and myelosuppressive drugs.5354 In patients with MDS, the reduced-intensity regimen results in full engraftment and recovery with less immediate toxic-ity,53 thereby extending eligibility for SCT to older persons. The approach relies on the graft-versus-leukemia effect more than ablation of malignant cells by the conditioning regimen, though its success in patients with relatively resistant high-risk CMML is unclear. Because of the high frequency of relapses46 in patients receiving standard cytoreductive regimens,46 it seems reasonable, at least for patients with high-risk CMML, to attempt induction of CR immediately before transplantation. The claimed advantage of SCT in low-risk patients and those transplanted early after diagnosis is based on results of retrospective studies or phase II clinical trials with small numbers of CMML patients who are highly selected,46 47 which complicates interpretation of the results. The absence of randomized studies leaves open the question of whether a delay of transplantation until disease progression would compromise the outcome. For MDS, modeling of the expected outcome of early transplantation suggested an advantage for patients with high-risk disease, whereas patients with low-risk disease benefited from delayed transplantation.55 In both situations, delay until progression to leukemia resulted in the worst out-come.55 Thus, patients with low-risk and intermediate-risk disease (by, e.g., MDAPS) may be best treated by supportive care and can be encouraged to participate in investigational clinical trials. Patients with intermediate-risk and high-risk CMML should be considered for SCT if a suitable donor is available. Although many treatment centers prefer a direct transplant procedure, an induction attempt followed by SCT may be a better choice in light of the high relapse rate in such patients and the availability of effective and safe induction therapy.

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