Table 1.

Evolution to secondary MDS/AML in AA

Study/YearPatients, nMedian age (range), yLocation, study period, designTreatment regimenMedian follow-up (range), yNo. of patients transformed to MDS/AML and, if reported, the median time to transformationProjected incidence of transformation to MDS/AML
de Planque et al12 /1989 209* 23 (1-73) Europe, 1975-1985, retrospective ATG, CsA, steroids 4.1 (2.0-10.9) Total (MDS or AML): n = 12; MDS or AL: 15% at 7 y 
MDS: n = 11, 4.6 (2.5-7.5) y; 
AL: n = 5 (4 with prior MDS), 5.0 (2.8-7.6) y 
Socié et al10 /1993† 860 29‡ (0.3-83) Europe, 1971-1991, prospective ATG + MP ± androgens 3.3‡ (0.1-14) Total (MDS or AML): n = 34; MDS: 9.6% (95% CI, 5.5% to 16.5%) at 10 y; 
MDS: n = 28, 4.3 (0.2-10.2) y; AL: 6.6% (95% CI, 3.6% to 11.8%) at 10 y 
AL: n = 15 (9 with prior MDS), 3.9 (0.6-9.6) y 
Socie et al95 /2007 840 26.8 (IQR, 15.4-46.6) Europe, 1990-2002, retrospective ATG + CsA, ± G-CSF 4.7 (NR) MDS: n = 24, 2.5 (IQR, 2-5.6) y; MDS: 4.3% at 10 y 
AML: n = 26, 2.2 (IQR, 0.9-5.4) y AML: 4.6% at 10 y 
Tichelli et al13 /1988 129 22 (1-73) Germany, 1976-1992, prospective ALG, norethandrolone NR Total (MDS or AML): n = 13; MDS: 26% (±8%) at 15 y 
Tichelli et al14 /1994 MDS: n = 13, 5 (1.8-13) y; 
AL: n = 8 (all with prior MDS) 
Tichelli et al15 /2011 192 46 (2-81) Germany, 2002-2008, prospective ATG/CsA ± G-CSF 11.7 (10.9-12.5) Total (MDS or AML): n = 9 8.5% (±3%) for G-CSF group; 
Tichelli et al139 /2019 8.2% (±3%) for non–G-CSF group at 15 y 
Führer et al97 /1998 86 9 (0.9-15) Germany/Austria, 1993-1997, prospective ALG, CsA, ± G-CSF NR MDS: n = 1; NR 
AL: n = 4; 
NR (0.3-1.6) 
Huang et al98 /2015 100§ 31 (5-76) China, 2012-2014, prospective CsA ± ATG NR Total (MDS or AML): n = 9; NR 
MDS: n = 9, 3 (0.6-7.2) y; 
AL: n = 2 (both with prior MDS) 
Li et al99 /2011 802 23 (3-74) China, 1991-2007, prospective ATG, CsA, G-CSF, androgens 6.8 (1-28.4) Total (MDS or AML): n = 19, 2.8 (1-20) y; 2.5% (95% CI, 1.5% to 4.1%) at 10 y 
MDS: n = 14; 
AML: n = 6 (1 with prior MDS) 
Kojima et al100 /2002 113 9 (1-18) Japan, 1992-1997, prospective ATG, CsA, danazol ± G-CSF 5.3 (3.75-8.9) Total (MDS or AML): n = 12, 4.6 (0.8-6.8) y 13.7% (±3.9%) at 8 y 
Ohara et al101 /1997 
Frickhofen et al102 /1991 84 32 (2-80) Germany, 1986-1989, prospective ATG, MP ± CsA 11.3 (9.4-13.4) Total (MDS or AML): n = 4, 8% at 11.3 y 
Frickhofen et al17 /2003 NR (6.6-9.5 y) 
Rosenfeld et al16 /2003 122 35 (NR) USA, 1989-1998, prospective ATG, CsA, steroids 7.2 (NR) MDS: n = 10||; NR 
AML: n = 3 
Paquette et al103 /1995 77* 42 (16-82) USA, 1977-1988, prospective ATG ± androgens, steroids, cyclosporine ∼5 (NR) Total (MDS or AML): n = 5, 4.1 (2.5-10.5) y 13% (±7%) at 10.5 y 
Locasciulli et al104 /2001 87 (IST + G-CSF) 19 (1-72) Italy, 1978-1991, retrospective IST + G-CSF 3.8 (0.5-10.8) Total (MDS or AML): n = 5, 2.1 (0.5-4.4) y; 9% at 5 y 
MDS: n = 3; 
AL: n = 2 
Locasciulli et al104 /2001 57 (IST alone) 26 (7-70) Italy, 1978-1991, retrospective IST (ATG, steroids, androgens, cyclosporine) 8.6 (0.4-19) Total (MDS or AML): n = 7, 1.0 (0.3-9.1) y; 7% at 5 y 
MDS: n = 5; 
AL: n = 2 
Townsley et al105 /2017 92 32 (3-82) USA, 2012-2015, prospective ATG + CsA + eltrombopag 1.9 (0.2-3.9) MDS: n = 3; N/A 
AML: n = 1 
Rogers et al77 /2019 314 9.8 (1-20.3) North America, 2002-2014, retrospective ATG + CsA 5 (NR) Total (MDS or AML): n = 6 NR 
Doney et al106 /1997 227 25 (1-74) USA, 1978-1986, retrospective ATG, oxymetholone, G-CSF NR (at least 5 y) Total (MDS or AML): n = 20 NR 
Bacigalupo et al107 /2000 100 16 (1-72) Italy, NR, prospective 4-drug: ALG, CsA, MP, G-CSF 3.9 (0.2-7.9) MDS: n = 4; NR 
AL: n = 2 
Study/YearPatients, nMedian age (range), yLocation, study period, designTreatment regimenMedian follow-up (range), yNo. of patients transformed to MDS/AML and, if reported, the median time to transformationProjected incidence of transformation to MDS/AML
de Planque et al12 /1989 209* 23 (1-73) Europe, 1975-1985, retrospective ATG, CsA, steroids 4.1 (2.0-10.9) Total (MDS or AML): n = 12; MDS or AL: 15% at 7 y 
MDS: n = 11, 4.6 (2.5-7.5) y; 
AL: n = 5 (4 with prior MDS), 5.0 (2.8-7.6) y 
Socié et al10 /1993† 860 29‡ (0.3-83) Europe, 1971-1991, prospective ATG + MP ± androgens 3.3‡ (0.1-14) Total (MDS or AML): n = 34; MDS: 9.6% (95% CI, 5.5% to 16.5%) at 10 y; 
MDS: n = 28, 4.3 (0.2-10.2) y; AL: 6.6% (95% CI, 3.6% to 11.8%) at 10 y 
AL: n = 15 (9 with prior MDS), 3.9 (0.6-9.6) y 
Socie et al95 /2007 840 26.8 (IQR, 15.4-46.6) Europe, 1990-2002, retrospective ATG + CsA, ± G-CSF 4.7 (NR) MDS: n = 24, 2.5 (IQR, 2-5.6) y; MDS: 4.3% at 10 y 
AML: n = 26, 2.2 (IQR, 0.9-5.4) y AML: 4.6% at 10 y 
Tichelli et al13 /1988 129 22 (1-73) Germany, 1976-1992, prospective ALG, norethandrolone NR Total (MDS or AML): n = 13; MDS: 26% (±8%) at 15 y 
Tichelli et al14 /1994 MDS: n = 13, 5 (1.8-13) y; 
AL: n = 8 (all with prior MDS) 
Tichelli et al15 /2011 192 46 (2-81) Germany, 2002-2008, prospective ATG/CsA ± G-CSF 11.7 (10.9-12.5) Total (MDS or AML): n = 9 8.5% (±3%) for G-CSF group; 
Tichelli et al139 /2019 8.2% (±3%) for non–G-CSF group at 15 y 
Führer et al97 /1998 86 9 (0.9-15) Germany/Austria, 1993-1997, prospective ALG, CsA, ± G-CSF NR MDS: n = 1; NR 
AL: n = 4; 
NR (0.3-1.6) 
Huang et al98 /2015 100§ 31 (5-76) China, 2012-2014, prospective CsA ± ATG NR Total (MDS or AML): n = 9; NR 
MDS: n = 9, 3 (0.6-7.2) y; 
AL: n = 2 (both with prior MDS) 
Li et al99 /2011 802 23 (3-74) China, 1991-2007, prospective ATG, CsA, G-CSF, androgens 6.8 (1-28.4) Total (MDS or AML): n = 19, 2.8 (1-20) y; 2.5% (95% CI, 1.5% to 4.1%) at 10 y 
MDS: n = 14; 
AML: n = 6 (1 with prior MDS) 
Kojima et al100 /2002 113 9 (1-18) Japan, 1992-1997, prospective ATG, CsA, danazol ± G-CSF 5.3 (3.75-8.9) Total (MDS or AML): n = 12, 4.6 (0.8-6.8) y 13.7% (±3.9%) at 8 y 
Ohara et al101 /1997 
Frickhofen et al102 /1991 84 32 (2-80) Germany, 1986-1989, prospective ATG, MP ± CsA 11.3 (9.4-13.4) Total (MDS or AML): n = 4, 8% at 11.3 y 
Frickhofen et al17 /2003 NR (6.6-9.5 y) 
Rosenfeld et al16 /2003 122 35 (NR) USA, 1989-1998, prospective ATG, CsA, steroids 7.2 (NR) MDS: n = 10||; NR 
AML: n = 3 
Paquette et al103 /1995 77* 42 (16-82) USA, 1977-1988, prospective ATG ± androgens, steroids, cyclosporine ∼5 (NR) Total (MDS or AML): n = 5, 4.1 (2.5-10.5) y 13% (±7%) at 10.5 y 
Locasciulli et al104 /2001 87 (IST + G-CSF) 19 (1-72) Italy, 1978-1991, retrospective IST + G-CSF 3.8 (0.5-10.8) Total (MDS or AML): n = 5, 2.1 (0.5-4.4) y; 9% at 5 y 
MDS: n = 3; 
AL: n = 2 
Locasciulli et al104 /2001 57 (IST alone) 26 (7-70) Italy, 1978-1991, retrospective IST (ATG, steroids, androgens, cyclosporine) 8.6 (0.4-19) Total (MDS or AML): n = 7, 1.0 (0.3-9.1) y; 7% at 5 y 
MDS: n = 5; 
AL: n = 2 
Townsley et al105 /2017 92 32 (3-82) USA, 2012-2015, prospective ATG + CsA + eltrombopag 1.9 (0.2-3.9) MDS: n = 3; N/A 
AML: n = 1 
Rogers et al77 /2019 314 9.8 (1-20.3) North America, 2002-2014, retrospective ATG + CsA 5 (NR) Total (MDS or AML): n = 6 NR 
Doney et al106 /1997 227 25 (1-74) USA, 1978-1986, retrospective ATG, oxymetholone, G-CSF NR (at least 5 y) Total (MDS or AML): n = 20 NR 
Bacigalupo et al107 /2000 100 16 (1-72) Italy, NR, prospective 4-drug: ALG, CsA, MP, G-CSF 3.9 (0.2-7.9) MDS: n = 4; NR 
AL: n = 2 

Rates of transformation to MDS/AML in series of AA patients treated with IST.

AL, acute leukemia; ALG, antilymphocyte globulin; ATG, antithymocyte globulin; CI, confidence interval; CsA, cyclosporine A; G-CSF, granulocyte-colony stimulating factor; IQR, interquartile range; IST, immunosuppressive therapy; MP, methylprednisolone; N/A, not applicable; NR, not reported; USA, United States of America.

*

Long-term survivors (>2 y) with records available.

†

Included some patients from the above study by de Planque et al.12 

‡

Mean value.

§

Patients with clinical information available.

||

MDS group included cytogenetic evolution.

Estimated from overall K-M curve.

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