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μg/kg as the maximum tolerated dose of plerixafor for this regimen. The 30-day induction mortality was 5.8% (n=4) and 60-day induction mortality was 13.0% (n=9).
Efficacy
Of 69 evaluable patients, the overall response rate was 43% (35% CR, 7% CRi, 1% PR), with a median time to best response of 1.9 months (2 cycles, range 0.9-7.9 months). The median response duration was 4.5 months, with a median follow-up time for the entire study group (based on survivors) of 9.9 months (range 5.4-24.8 months). Median OS was 11.2 months (95%CI: 8.5 months, 13.9 months) (Figure 3A). As expected, the medi- an OS for responders was significantly longer (18 months; 95%CI: 10.5-25.4 months) than for non-responders (5.0 months; 95%CI: 1.4-8.6 months) (P<0.0001). Prior treat- ment with azacitidine was the strongest independent pre- dictor of OS (adjusted hazard ratio 3.1, 95%CI: 1.3-7.3; P=0.008) (Figure 3B). The median survival of patients pre- viously treated with azacitidine was also much shorter than for previously untreated patients (2.5 months, 95%CI: 1.1-3.8 months vs. 12.6 months, 95%CI: 9.5-15.7 months; P=0.001). In addition, whereas 52% of HMA treatment-naïve patients responded to treatment (46%/6% CR/CRi), only 14% of patients previously treated with an HMA achieved a response (0%/14% CR/CRi; P=0.002). Finally, adverse karyotype did not predict overall response (P=0.31) and 53% of patients with adverse cytogenetics achieved responses (43% CR, 7% CRi, 3% PR). Median OS was 10.9 months in 59 patients without a TP53 muta- tion and 18.1 months in the 10 patients with TP53 muta- tion, but this result was not statistically significant, proba- bly due to the small sample size. In multivariate analysis, however, adverse karyotype, as well as baseline bone mar- row blasts more than 54%, were significant predictors of poor OS. Neither therapy-related AML nor the presence of an antecedent hematologic disorder was a significant pre- dictor of response; 10 patients with therapy-related AML (32%) and 14 patients (45%) with an antecedent hemato- logic disorder achieved CR/CRi. There were no significant differences in ORR or OS based on plerixafor dose level (P=0.55 and P=0.19, respectively) or treatment schedule (A
AB
vs. B; P=0.71 and P=0.53, respectively), but the study was not powered for these comparisons.
After discontinuation of study treatment, 28 patients (42%) received further anti-leukemia therapies. Of these 28 patients, 8 achieved first or second remission with stan- dard cytarabine/daunorubicin induction (n=5), additional decitabine (n=2), or elacytarabine (n=1). Thirteen patients (20%) underwent hematopoietic stem cell transplantation, of whom 9 were in remission, one was in partial remis- sion, and 3 were not in remission at the time of transplant.
Correlative studies
The primary goal of the correlative studies was to assess the ability of plerixafor to induce mobilization. As shown in Figure 4, treatment with plerixafor resulted in signifi- cant mobilization of leukemic stem and progenitor cells, but not as robustly and consistently as predicted. The mobilizing effect of plerixafor was highly significant (P=0.0221) among clinical responders (n=21) versus non- responders (n=19) (Figure 4B). Patients who received pler- ixafor combined with decitabine starting in their first cycle of treatment (B cohorts) were observed to have their most significant mobilizations during plerixafor-contain- ing cycles (n=26; P=0.0318) (Figure 4C and D). As plerix- afor is a CXCR4 antagonist that is expected to induce cell cycle entry of LSCs via loss of CXCR4-SDF1 interaction, we evaluated CXCR4 expression prior to plerixafor (Figure 5A), as well as cell cycle status before and after exposure to plerixafor (Figure 5C). As expected, we found that, within the responder group, plerixafor was more likely to mobilize CXCR4+ cells (Figure 5A and B). Interestingly, no significant differences were found for the non-responder group when evaluating mobilization with respect to CXCR4 expression (Online Supplementary Figure S1A). In addition, we found that plerixafor was more like- ly to increase the cycling of stem/progenitor cells, as meas- ured by Ki-67 staining (Figure 5C and D). However, even though we observed that mobilizers tended to have increased proportions of cycling cells, we did not find dif- ferences in the duration of response or time to relapse between patients with and without increased cycling (Online Supplementary Figure S1B).
Figure 3. Overall survival (OS) for all evaluable patients in the study. (A) Kaplan-Meier OS curves for all patients (n=69) enrolled on the study. Median OS 11.2 months (95% CI: 8.6 months, 13.8 months). (B) OS for patients stratified by prior hypomethylating agent (HMA) therapy. No prior HMA (n=55), median OS 12.6 months (95%CI: 9.2, 15.9 months); prior hypomethylating agent (n=14), median OS 2.5 months (95%CI: 1.1, 3.8 months); P=0.0008 by log-rank test. PD: plerixafor + decitabine; D: decitabine.
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