Page 56 - 2019_02-Haematologica-web

A. Contejean et al.
vSAA (HR 3.02 (1.12;8.12), P=0.029), or with a high base- line Charlson comorbidity index score (HR 1.38 (1.11;1.72), P=0.0043) or performance status (HR 1.77 (1.11;2.83), P=0.017). We also found a trend pointing to an association between age and mortality (HR per year 1.05 (0.99;1.11), P=0.079). Due to the small number of events, our multivariable analysis only included the three most relevant factors. We consequently found that age (OR 1.07 (1.01;1.14), P=0.03), Charlson comorbidity index (HR 1.34 (1.07;1.67), P=0.01) and vSAA (HR 3.67 (1.51;8.91), P=0.004) were independently associated with mortality (Table 6). Regarding the impact of treatment on mortality, Table 3 shows that after adjustment for treatment line, disease severity and performance status, the benefits observed in terms of response with ATG-CsA were not associated with reduced mortality (HR 0.44 (0.13;1.45), P=0.18). Likewise, we found no statistical difference in overall survival between patients who received first-line horse ATG in comparison with rabbit ATG (HR 4.7 (0.4;52.6), P=0.2) or in mortality between patients over 70 years old who received first-line ATG-CsA in comparison with other treatments (HR 0.17 (0.02;1.28), P=0.08).
Discussion
This study focused on current real-life management of AA in the elderly in France. This is, to our knowledge, the largest cohort specifically addressing the question of AA management in the elderly.
Our population comprised patients with a median age of 68.5 years (maximum 89 years) with an even sex ratio, although previous epidemiological studies suggested a feminine predominance in older patients with AA.7 Although patients mostly had SAA or vSAA (57%), nine patients did not require transfusion during the first months following treatment initiation. They had few comorbidities (median Charlson comorbidity index of 2) and were fit (median performance status 1). Of particular notice, although PMN count or hemoglobin may be nor- mal in some patients at diagnosis, all patients had throm- bocytopenia (maximum platelets count 82x109/L).
We reported 8% of cytogenetic abnormalities at diagno- sis, close to that described in literature (4-5%).11,24,25 We found two Y deletions, an abnormality frequently encoun- tered in the elderly. Others were: one trisomy 8, one split of IgH locus, one deletion 13p and one deletion 4q. Trisomy 8 is known to be seen in AA,25,26 and may be the most frequent cytogenetic aberration in this pathology.11,27 Abnormalities of IgH locus have not been reported in AA, but chromosome 14 aberrations can be seen in AA.27
Table 5. Treatment tolerance comparing ATG-CsA regimens with others. ATG-CsA (n=60)
Abnormalities of chromosome 13 have been reported but affecting more often the long arm (13q).28 Finally, deletion 4q has not before been described in this pathology.
This observational study highlights the great hetero- geneity in the choice of treatment in this population. In first line, half of the patients received ATG-CsA, including five with eltrombopag, although combined treatments with eltrombopag in first line is not recommended yet.14 This proportion is consistent with previously reported series.13 One fifth of the patients received CsA alone. Patients receiving ATG-CsA in front line were significant- ly younger and mostly women. We could not explain this difference in sex ratio. Conversely, other parameters, which could be decisive in treatment choice, like perform- ance status, Charlson comorbidity index or disease sever- ity, did not differ between groups. Analysis of all treat- ment lines lets us see that most of those were immuno- suppressive treatments (58%), mainly ATG-CsA combina- tions. The majority of ATG-CsA were performed in first line (73%). Patients receiving ATG-CsA after the first line (n=16) were younger (maximum 70 years). Six of them had already received this treatment in first line; while 10 patients had previously received another first line therapy. CsA represented 14% of treatment lines, as androgens. Eltrombopag was given as a monotherapy in 9% of cases. As reported in literature,13 AHSCTs were marginal in this population since two patients received this treatment: the first one for a clonal evolution with 7q- who died from invasive fungal infection; and the second who is alive 36 months after AHSCT and was refractory to two lines before graft including ATG-CsA. Despite no recommen- dations, 21% of treatment lines went along with EPO and 23% with G-CSF. EPO and G-CSF were considered to be supportive care treatments and not treatment lines.
The global response rate was 38%, all lines combined. Time to best response was long: 151 days (4.9 months). We observed that in first line, 47% of patients reached response, with 32% of CR. Only 6 patients obtained CR
Table 4. Impact of treatment on overall response, after adjustment for treatment line, disease severity and performance status (multivariable analysis, with ATG-CsA as a baseline).
ATG-CsA
CsA alone
Eltrombopag alone
Androgens alone
Other
OR (CI95%)
1
0.35 (0.13;0.96)
0.12 (0.03;0.54)
0.17 (0.05;0.58)
0.24 (0.09;0.63)
P
1
0.042
0.0057
0.0047
0.0038
ATG: Anti-thymocyte Globulin; CI: Confidence Interval; CsA: Cyclosporine-A; OR: Odds Ratio.
Infectious complications
Cardiovascular complications Acute kidney failure
Hemorrhagic complications Hepatic or digestive complications Neurological complications
no: ATG: Anti-Thymocyte Globulin; CsA: Cyclosporine-A.
72%
32% 43% 18% 23% 7%
Others (n=124)
24%
15% 22% 15% 19% 4%
P ATG-CsA ≥70 years (n=16) <0.0001 88%
0.01 31% 0.003 50% 0.62 19% 0.56 31% 0.48 13%
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