Abstract

Background

Minimal residual disease (MRD) has been recognized as a strong, independent predictor of increased relapse risk and poor outcome for patients with acute myeloid leukemia (AML) in first complete remission (CR) undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). As the relationship between MRD and outcome is less studied for AML patients undergoing nonmyeloablative (NMA) HCT, we herein conducted a comparative analysis to assess this association relative to that seen in MA HCT.

Patients and Methods

We studied 272 consecutive patients receiving NMA (n=63) or MA (n=209) HCT for AML in first CR or CR with incomplete blood count recovery (CRi) between May 2006 and May 2012. Pre-HCT bone marrow aspirates were obtained in all patients and analyzed by routine karyotyping and ten-color flow cytometry. MRD was identified as a cell population showing deviation from normal antigen expression patterns as compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Data are current as of April 1, 2013.

Results

Baseline characteristics of the study cohort are summarized in Table 1. Patients undergoing NMA HCT were significantly older than those undergoing MA HCT (p<0.001), more often were male (p=0.03), had more comorbidities (p<0.001), more often had secondary leukemias (p=0.05), and more often had incomplete blood count recovery at the time of HCT (p<0.001). Sixteen NMA patients (25.4%) and 40 MA patients (19.1%) were MRDpos, with medians of 0.31% (range: 0.02-2.8%) and 0.29% (0.007-7.8%) abnormal blasts for MRDpos NMA and MA patients, respectively. Three-year estimates of relapse among NMA patients were 31% (18-44%) and 64% (35-82%) for MRDneg and MRDpos patients, respectively, and 21% (15-29%) and 53% (37-68%), respectively, among MA patients (Figure 1A). Among NMA patients, the 3-year estimates of OS were 53% (37-66%) and 49% (21-73%) for MRDneg and MRDpos patients, respectively; among MA patients, 3-year OS was estimated to be 74% (65-80%) and 36% (20-51%), respectively (Figure 1B). This unexpectedly similar outcome in OS for MRDneg and MRDpos NMA patients was largely accounted for by the considerably higher non-relapse mortality (NRM) in MRDneg patients (29% [17-42%]) compared to MRDpos patients (0%), which was the reverse of findings in MRDneg and MRDpos MA patients (8% [5-13%] vs. 21% [10-34%], respectively; Figure 1C). Hazard ratio analysis confirmed a highly statistically significant difference between MA and NMA patients in the association of MRD status with NRM (p<0.001), but not with relapse (p=0.45). There was also evidence of a differential association of MRD status with OS (p=0.03). After adjustment for HCT type (NMA vs MA), age, cytogenetic risk, type of AML, number of cycles of induction chemotherapy, type of consolidation therapy, pre-HCT karyotype, pre-HCT blood counts, and HCT-comorbidity index, being MRDpos was associated with increased risk of relapse (HR=3.31 [1.91-5.73], p<0.001).

Table 1
NMA HCTMA HCT
MRDneg (n=47)MRDpos (n=16)MRDneg (n=169)MRDpos (n=40)
Median Age at HCT (range), years 62.2 (20.0-75.0) 63.7 (33.1-74.0) 44.7 (0.6-69.7) 47.6 (2.5-66.8) 
Male Gender, % 61.7% 87.5% 51.5% 57.5% 
Cytogenetics, %     
 Favorable 6.7% 0% 4.2% 0% 
 Intermediate 71.1% 50.0% 72.1% 51.3% 
 Adverse 22.2% 50.0% 23.6% 48.7% 
Secondary AML, % 42.6% 62.5% 29.0% 55.0% 
Pre-HCT Consolidation Therapy, %     
 No 8.5% 25.0% 16.0% 37.5% 
 Yes 91.5% 75.0% 84.0% 62.5% 
Median CR Duration (range), days 115 (35-318) 76.5 (35-356) 121 (18-465) 93 (16-383) 
Pre-HCT Peripheral Blood Counts, %     
 Recovered 72.3% 68.9% 91.7% 85.0% 
 Not recovered 27.7% 31.3% 8.3% 15.0% 
Pre-HCT Routine Cytogenetics, %     
 Normalized karyotype 51.1% 37.5% 52.7% 47.5% 
 Abnormal karyotype 6.4% 43.8% 8.9% 27.5% 
 Missing/non-informative data 42.6% 18.8% 38.5% 25.0% 
Median HCT Comorbidity Index (range), days 3 (0-11) 4 (2-10) 2 (0-6) 2 (0-7) 
Unrelated Donor, % 72.3% 62.5% 65.1% 72.5% 
NMA HCTMA HCT
MRDneg (n=47)MRDpos (n=16)MRDneg (n=169)MRDpos (n=40)
Median Age at HCT (range), years 62.2 (20.0-75.0) 63.7 (33.1-74.0) 44.7 (0.6-69.7) 47.6 (2.5-66.8) 
Male Gender, % 61.7% 87.5% 51.5% 57.5% 
Cytogenetics, %     
 Favorable 6.7% 0% 4.2% 0% 
 Intermediate 71.1% 50.0% 72.1% 51.3% 
 Adverse 22.2% 50.0% 23.6% 48.7% 
Secondary AML, % 42.6% 62.5% 29.0% 55.0% 
Pre-HCT Consolidation Therapy, %     
 No 8.5% 25.0% 16.0% 37.5% 
 Yes 91.5% 75.0% 84.0% 62.5% 
Median CR Duration (range), days 115 (35-318) 76.5 (35-356) 121 (18-465) 93 (16-383) 
Pre-HCT Peripheral Blood Counts, %     
 Recovered 72.3% 68.9% 91.7% 85.0% 
 Not recovered 27.7% 31.3% 8.3% 15.0% 
Pre-HCT Routine Cytogenetics, %     
 Normalized karyotype 51.1% 37.5% 52.7% 47.5% 
 Abnormal karyotype 6.4% 43.8% 8.9% 27.5% 
 Missing/non-informative data 42.6% 18.8% 38.5% 25.0% 
Median HCT Comorbidity Index (range), days 3 (0-11) 4 (2-10) 2 (0-6) 2 (0-7) 
Unrelated Donor, % 72.3% 62.5% 65.1% 72.5% 
Conclusion

The negative impact of MRD on post-transplant relapse risk among AML patients in CR1 undergoing NMA HCT is similar to the negative impact seen in patients undergoing MA HCT. Because of the high rate of NRM among MRDneg NMA patients the survival difference between MRDneg and MRDpos patients was much larger in MA than NMA patients in this analysis.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.