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Aplastic anemia in the elderly
Table 6. Impact of baseline characteristics on mortality.
Univariable analysis Multivariable analysis
Male
Age (per year)
Charlson comorbidity index (for each one-point increase)
Performance status (for each one-point increase)
Weight (for each one-kg increase)
SAA
vSAA
HR (CI95%)
1.74 (0.76;3.99)
P HR (CI95%) P 0.19 - -
1.05 (0.99;1.11) 1.38 (1.11;1.72) 1.77 (1.11;2.83) 1.03 (1;1.07) 1.24 (0.45;3.45) 3.02 (1.12;8.12) 0.66 (0.09;5)
0.079 0.0043 0.017 0.059
1.07 (1.01;1.14) 0.03 1.34 (1.07;1.67) 0.01
- - 0.68 - -
0.029 3.67 (1.51;8.91) 0.004 0.69 - -
- -
PNH clone ≥ 5%
CI: Confidence Interval; HR: Hazard Ratio; PNH: Paroxysmal Nocturnal Hemoglobinuria; SAA: Severe Aplastic Anemia; vSAA:Very Severe Aplastic Anemia.
after first line. The global response rate was higher with ATG-CsA (62% all lines combined, 70% in first line). These results are similar to results in younger patients (global responses of 60% to 80%).29,30 In this study, we found no difference in first line ORR between horse and rabbit ATG. Older patients (>70 years) responded well to ATG-CsA, with a global response rate of 81% of (50% CR and 31% PR). Global response after a CsA course was 35%, all lines combined, and 39% in first line, as in a younger population.31 Responses to eltrombopag (22%) or androgen (21%) were lower. Although defined with dif- ferent criteria and in a broader population, Lengline et al. found a higher response rate with eltrombopag than us.32 Baseline Charlson comorbidity index and performance status were associated with a lower response rate. After adjustment for treatment line, performance status and dis- ease severity, we found that ATG-CsA was associated with a better response. Conversely, multivariable analysis showed that patients treated with CsA alone, eltrom- bopag or androgens were worse responders in comparison with ATG-CsA.
Treatments were well tolerated in this population, with very little treatment-related mortalities, although this should be interpreted with caution due to our retrospec- tive design. Complications were mostly infectious, partic- ularly after immunosuppressive treatments, and especially ATG-CsA, followed by acute kidney failure, almost exclu- sively seen in patients receiving CsA. Conversely, eltrom- bopag carries a good tolerance profile in our study. Among patients who died from hemorrhagic complications, none were treated with ATG-CsA, and only 3 in 9 patients who died from infectious complications were under an ATG- CsA regimen. Thus, this treatment, although exposing to more infectious events, rarely conducted to death from infectious origin. Interestingly, patients over 70 years tol- erated ATG-CsA as well as younger patients, with one death from sepsis.
Survival was noticeably better than in recently pub- lished data,13,33 with a median survival of 7.36 years and three-year survival of 74.7%. Some of the baseline charac- teristics were associated with mortality: age, Charlson comorbidity index and vSAA in comparison to SAA and mild AA. The positive impact of ATG-CsA on response rates did not translate into better survival after adjustment for treatment line, performance status and disease severi- ty. Likewise, overall survival did not differ between patients over 70 years who received ATG-CsA in first line in comparison with other treatments as well as in patients receiving horse ATG in comparison with rabbit ATG in
first line. It is possible that our cohort was too small to reach significance in survival for patients receiving ATG- CsA and in the other subgroups of our study. Nevertheless, supportive care optimization of hematolog- ical patients with cytopenias might also explain the observed survival even in patients with refractory disease. Moreover, death in older patients may be due to causes unrelated to the underlying disease, even in the AA popu- lation.7
Our study has a number of limitations. Firstly, its retro- spective design and case identification strategy may bring some bias, particularly a lack of exhaustivity of our data or patient identifications. We also may have selected more complicated cases by using the data of the French Reference Center for Aplastic Anemia. However, the sys- tematic identification of cases using data from patholo- gists from each center may have limited this bias. Secondly, the great heterogeneity of treatments in our population did not allow us to conclude on specific regi- mens like CsA-androgen or CsA-eltrombopag. Specific studies assessing these combinations in this population should be conducted. Thirdly, we found a low rate of clonal evolution with four occurrences. This is less than previously reported,7 and may be due to the relatively short median follow up of our cohort. Fourthly, multivari- able analyses were limited in the number of adjustment variables, to fit with the number of events. However, these variables were selected as the most pertinent and susceptible to bias the univariate analyses results. For the same reason, we were not able to adjust the response or mortality predicting factors on age, although age was associated with survival. We chose to adjust on treatment line, disease severity and performance status because these factors were, for us, the most relevant in this con- text. Lastly, the retrospective design and data collection of files may limit interpretation of tolerance data, since less serious adverse events may have been neglected in patient reports. Nevertheless, it is probable that most of the seri- ous adverse events have been well reported.
In conclusion, our study shows that current therapeutic choices in elderly patients with AA are very heteroge- neous in France, and are not based on objective selection criteria, such as performance status or comorbidities. The impact of the first-line treatment regimen choice in terms of response underlies the need for strong recommenda- tions in this population. Our analysis stresses that some of the patient characteristics are associated with mortality: age, comorbidities, and very severe AA. Given that sur- vival in the elderly is naturally shorter than in younger
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