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Myelodysplastic Syndrome Patients with Disease Progression after Cytoreductive Therapy Have Poor Survival and High Non-Relapse Mortality after Full-Intensity Allogeneic Hematopoietic Cell Transplantation
Background: Many patients with myelodysplastic syndrome (MDS) undergo cytoreductive chemotherapy to reduce the marrow blast count prior to allogeneic hematopoietic cell transplantation (HCT). While pre-HCT disease burden correlates with post-HCT outcome, a dynamic approach of assessing changes in blast count with therapy has not been systematically explored.
Methods: Results of 54 consecutive patients transplanted between 2005-2012 for MDS (43 de novo, 11 secondary) with full-intensity conditioning regimens (94% with busulfan /cyclophosphamide) were analyzed. The median age was 50 years (range 20-66). Donors were siblings (33%) or unrelated (67%); 78% of patients received marrow and 22% peripheral blood progenitor cells. Recursive partitioning analysis (RPA) was used to identify groups that are prognostic for overall survival (OS) based on pre-HCT chemotherapy and change in blast count. The association of RPA group with outcome was examined.
Results: RPA identified three groups: patients who did not receive pre-HCT cytoreduction (G1), those who did with subsequent stable/decreased (G2) or increased (G3) blast count prior to HCT. These groups were similar with respect to demographic, disease, and transplant variables, as well as comorbidity scores (HCT-CI).
Though the grade and incidence of GVHD and relapse were similar, OS (Figure, P = 0.02, log-rank) and NRM (P = 0.08, Gray test) were inferior for patients who had an increase in blast count after pre-HCT cytoreduction. Three-year OS was 54%, 43%, and 12%, respectively, for G1, G2, and G3; 3-year NRM was 31%, 34%, and 81%. Mortality at 100 days was 23%, 7%, and 46% for G1, G2, and G3, respectively (P = 0.16). A clear pattern for cause of NRM in G3 versus G1/G2 could not be discerned.
Pre-HCT blast count and comorbidities were not associated with OS in univariate analysis (Table). In multivariate analysis, pre-HCT chemotherapy with an increase in blast count remained associated with a worse survival relative to no prior chemotherapy (HR 3.08, 95% CI 1.13-8.43, P = 0.028.
Conclusions: Counterintuitively, the inferior survival of G3 was not due to relapse, but mainly NRM, particularly early mortality, despite similar HCT-CI scores. This result suggests that those who progress despite pre-HCT chemotherapy with an unacceptably high risk of NRM, may not benefit from HCT. This analysis cannot determine if pre-HCT cytoreduction is beneficial or detrimental, and should be carefully assessed in prospective studies.
Variable
| HR
| 95% CI
| P-value
|
RPA group
|
|
|
|
G1 (no cytoreduction) | 1
|
|
|
G2 (Cytoreduction w/ stable/decreasing blasts) | 1.15
| 0.45-2.98
| 0.77
|
G3 (Cytoreduction w/ increasing blasts) | 3.03
| 1.11-8.28
| 0.03
|
De novo vs. secondary MDS
| 3.52
| 1.07-11.6
| 0.039
|
LDH >330 IU/L at HCT | 2.69
| 1.26-5.73
| 0.01
|
Blasts at HCT (continuous) | 1.05
| 0.98-1.12
| 0.16
|
HCT-CI score
|
|
|
|
Int vs. Low | 1.43
| 0.62-3.32
| 0.4
|
High vs. Low | 0.97
| 0.39-2.45
| 0.95
|
