Long Term Survival after ASCT for AML: Multivariate Analysis Shows Adverse Effect of Collecting and Infusing Larger Numbers of CD 34 Positive Cells.
Authors: Sarkodee-Adoo Clarence B. , Stein Anthony S. , O’Donnell Margaret R. , Bhatia Ravi M. , Bolotin E. , Chang K. P. , Kirschbaum Mark , Kogut Neil , Nademanee Auayporn , Parker Pablo , Pullarkat Vinod , Snyder David , Spielberger Ricardo , Slovak Marilyn L. , Alvarnas Joseph , Fridey Joy , Schriber Jeffrey , Smith Eileen , Dagis Andy , Land J. , Palmer J. , Vora N. , Forman Stephen 
Published: April 2020

INTRODUCTION: The major cause of failure after ASCT for AML in 1st remission is relapse. The collection/ infusion of more CD 34 + cells results in earlier engraftment, but its effect on relapse rates is unknown.

METHODS: Between 2/95 and 9/03, 87 patients with AML in 1st CR underwent ASCT on two sequential IRB-approved trials. Patients with APL, high-risk cytogenetics, or intermediate-risk cytogenetics and a sibling donor were preferentially treated on alternative protocols. Patients received two cycles of ara C (3 g/m2/12h x 8) and idarubicin 12mg/m2/d x 3 (one cycle ara C 2g/m2/12h x 8 if age 55–60). (Nine patients did not receive idarubicin).The 2nd cycle, followed by GCSF 10ug/kg, served as mobilization. All collected cells were infused. Conditioning utilized TBI/VP-16/cyclophosphamide (n = 47) or (AUC-targeted) busulfan/TBI/VP-16 (n = 40). Remission status (morphology; flow cytometry; normal cytogenetics) was confirmed in bone marrow samples prior to mobilization.

RESULTS: 5- year survival rates were 72% (95% CI 62–81%) overall and 68% (95% CI 56–77%) event-free (figure). Mobilization yielded 4.07 x 106 CD 34+ cells/kg (median; range 1.1– 45.08 x 106). Engraftment to ANC 500/ul occurred at 11 days (median; range 8–22), and to (non-transfused) platelet count of 20,000/ul at 22 days (median; range 7–183). In multivariable Cox regression analysis (model fit p-value 0.0007), earlier engraftment was associated with high versus standard dose ara C induction (1.77 times faster; p = 0.02), and graft CD 34+ cell content (1.06 times faster per 106 /kg; p = 0.001). By multivariable Cox proportional-hazards regression, (model fit p-value = 0.01) the number of CD 34+ cells collected/ infused and the time between remission and consolidation were both predictive of shorter event-free survival. An increase of 106 in the number of CD34+ cells was associated with a 1.06 factor increase in the probability of death or relapse (95% CI 1, 1.11, p = 0.04). Each month’s delay between remission and consolidation increased the probability of death or relapse by a factor of 1.22 (95% CI 1.02, 1.47, p = 0.03). The leukocyte count at diagnosis was associated with longer event-free survival (0.98 times per 1000 cells/ul), (95% CI 0.96, 1.00, p = 0.05). Age, sex, the presence of extramedullary disease, FAB subtype, cytogenetic risk group, type (high versus conventional dose ara-C) and number of induction cycles, use of idarubicin in consolidation, conditioning regimen, and IL-2 administration after transplant were not correlated with survival or event-free survival.

CONCLUSION: In this study, the collection and infusion of more CD 34+ cells resulted in shortened relapse-free survival, despite an initial favorable impact on engraftment times. Longer time between remission and consolidation also adversely influenced relapse-free survival.

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