J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Review

Volume 13, Number 3, June 2024, pages 61-70

Acquired Aplastic Anemia Therapies: Immunosuppressive Therapy Versus Alternative Donor Hematopoietic Cell Transplantation

**Table 1.** Modified Camitta Criteria to Assess Severity of Aplastic Anemia
	Diagnostic criteria
Severe aplastic anemia (SAA)	Bone marrow cellularity < 25% (or 25-50% if < 30% of residual cells are hematopoietic) and two of the following: 1) Peripheral blood absolute neutrophil count (ANC) < 0.5 × 10⁹/L; 2) Peripheral blood platelet count < 20 × 10⁹/L; or 3) Peripheral blood reticulocyte count < 60 × 10⁹/L
Very severe aplastic anemia (VSAA)	Criteria for SAA and ANC < 0.2 × 10⁹/L
Non-severe aplastic anemia (NSAA)	Bone marrow cellularity < 25% (or 25-50% if < 30% of residual cells are hematopoietic) and peripheral blood cytopenia not fulfilling criteria for SAA or VSAA

Table 1. Modified Camitta Criteria to Assess Severity of Aplastic Anemia

Diagnostic criteria

Severe aplastic anemia (SAA)

Bone marrow cellularity < 25% (or 25-50% if < 30% of residual cells are hematopoietic) and two of the following: 1) Peripheral blood absolute neutrophil count (ANC) < 0.5 × 10⁹/L; 2) Peripheral blood platelet count < 20 × 10⁹/L; or 3) Peripheral blood reticulocyte count < 60 × 10⁹/L

Very severe aplastic anemia (VSAA)

Criteria for SAA and ANC < 0.2 × 10⁹/L

Non-severe aplastic anemia (NSAA)

Bone marrow cellularity < 25% (or 25-50% if < 30% of residual cells are hematopoietic) and peripheral blood cytopenia not fulfilling criteria for SAA or VSAA

**Table 2.** Aplastic Anemia Versus Hypoplastic Myelodysplastic Syndrome
	Aplastic anemia	Hypoplastic myelodysplastic syndrome
Dysplasia	Erythroid lineage only	Bilineage/trilineage; granulocytic, megakaryocytic also
Blasts	None	Present-normal or increased
Abnormal localization of immature precursors	No	Yes
Cytogenetics	6p uniparental disomy, -7/deletion 7q, +8, +15	-5/deletion 5q, -7/deletion 7q, +8

Table 2. Aplastic Anemia Versus Hypoplastic Myelodysplastic Syndrome

Aplastic anemia

Hypoplastic myelodysplastic syndrome

Dysplasia

Erythroid lineage only

Bilineage/trilineage; granulocytic, megakaryocytic also

Blasts

None

Present-normal or increased

Abnormal localization of immature precursors

Yes

Cytogenetics

6p uniparental disomy, -7/deletion 7q, +8, +15

-5/deletion 5q, -7/deletion 7q, +8

**Table 3.** RACE^a Conducted Between 2015 and 2019 in Patients With Acquired Severe or Very Severe Aplastic Anemia Aged 15 Years or Older With Karnofsky Performance Status at Least 50-60% or Greater
	Group A	Group B
^aRandomized multicenter trial of horse anti-thymocyte globulin (ATG) + cyclosporine with or without EPAG as first line. OS: overall survival; NGS: next-generation sequencing: CR: complete remission; EPAG: eltrombopag; IV: intravenous; PO: per os; CI: confidence interval.
Therapy	Horse ATG 40 mg/kg/day × 4 days IV + cyclosporine PO for 12 months with taper over next 12 months and discontinuation at 24 months	EPAG 150 mg PO, day 14 to 6 months, or to 3 months if in CR + horse ATG 40 mg/kg/day × 4 days IV + cyclosporine for 12 months with taper over next 12 months and discontinuation at 24 months
Number of patients	101	95
Age, median (range) years	52 (15 - 81) years	55 (16 - 77) years
Response at 3 months
Complete response	10%	22%
Overall response	31%	59%
Response at 6 months
Complete remission	20%	32%
Overall response	41%	68%
Complete remission at 12 months	33%	52%
Median time to first response	8.8 months	3 months
Number of patients who had stem cell transplantation	12 patients	11 patients
Relapse at 18 months	11% (95%CI: 2 - 20)	19% (95% CI: 9 - 29)
2-year event-free survival	34% (95% CI: 24 - 44)	46% (95% CI: 36 - 57)
2-year overall survival	85% (95% CI: 78 - 92)	90% (95% CI: 82 - 97)
Multivariate analysis for worse OS and relapse risk	Age > 40 years	Age > 40 years
Percentage of patients with NGS somatic mutations at diagnosis	29%	31%
Percentage of patients with NGS somatic mutations at 6 months	66%	51%

Table 3. RACE^a Conducted Between 2015 and 2019 in Patients With Acquired Severe or Very Severe Aplastic Anemia Aged 15 Years or Older With Karnofsky Performance Status at Least 50-60% or Greater

Group A

Group B

^aRandomized multicenter trial of horse anti-thymocyte globulin (ATG) + cyclosporine with or without EPAG as first line. OS: overall survival; NGS: next-generation sequencing: CR: complete remission; EPAG: eltrombopag; IV: intravenous; PO: per os; CI: confidence interval.

Therapy

Horse ATG 40 mg/kg/day × 4 days IV + cyclosporine PO for 12 months with taper over next 12 months and discontinuation at 24 months

EPAG 150 mg PO, day 14 to 6 months, or to 3 months if in CR + horse ATG 40 mg/kg/day × 4 days IV + cyclosporine for 12 months with taper over next 12 months and discontinuation at 24 months

Number of patients

101

Age, median (range) years

52 (15 - 81) years

55 (16 - 77) years

Response at 3 months

Complete response

10%

22%

Overall response

31%

59%

Response at 6 months

Complete remission

20%

32%

Overall response

41%

68%

Complete remission at 12 months

33%

52%

Median time to first response

8.8 months

3 months

Number of patients who had stem cell transplantation

12 patients

11 patients

Relapse at 18 months

11% (95%CI: 2 - 20)

19% (95% CI: 9 - 29)

2-year event-free survival

34% (95% CI: 24 - 44)

46% (95% CI: 36 - 57)

2-year overall survival

85% (95% CI: 78 - 92)

90% (95% CI: 82 - 97)

Multivariate analysis for worse OS and relapse risk

Age > 40 years

Percentage of patients with NGS somatic mutations at diagnosis

29%

31%

Percentage of patients with NGS somatic mutations at 6 months

66%

51%

**Table 4.** Clonal Evolution to Secondary MN in Nontransplanted AA Patients
IST: immunosuppressive therapy; MN: myeloid neoplasm; AA: aplastic anemia; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; MPN: myeloproliferative neoplasm; HLA: human leukocyte antigen; IQR: interquartile range; CR: complete response.
N = 882 patients
10-year cumulative incidence of MN overall	12.80%
10-year cumulative incidence of MN for CR vs. no CR with IST	8.5% vs. 15.7%, P = 0.02
10-year cumulative incidence of MN for >35 years vs ≤ 35 years of age	20.6% vs. 6.6%, P < 0.001
Median time from diagnosis to MN	4.5 years (IQR: 1.8 - 7.7 years)
MN type	MDS 75%
	AML 18%
	MDS/MPN 7%
Clonal burden at diagnosis vs. at time of MN diagnosis	20% vs. 30%, P = 0.001
Mutations at AA diagnosis vs. at the time of MN progression	BCOR/L1, PIGA, HLA mutations decreased vs. myeloid mutations ASXL1, RUNX1, SETBP1 increased

Table 4. Clonal Evolution to Secondary MN in Nontransplanted AA Patients

IST: immunosuppressive therapy; MN: myeloid neoplasm; AA: aplastic anemia; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; MPN: myeloproliferative neoplasm; HLA: human leukocyte antigen; IQR: interquartile range; CR: complete response.

N = 882 patients

10-year cumulative incidence of MN overall

12.80%

10-year cumulative incidence of MN for CR vs. no CR with IST

8.5% vs. 15.7%, P = 0.02

10-year cumulative incidence of MN for >35 years vs ≤ 35 years of age

20.6% vs. 6.6%, P < 0.001

Median time from diagnosis to MN

4.5 years (IQR: 1.8 - 7.7 years)

MN type

MDS 75%

AML 18%

MDS/MPN 7%

Clonal burden at diagnosis vs. at time of MN diagnosis

20% vs. 30%, P = 0.001

Mutations at AA diagnosis vs. at the time of MN progression

BCOR/L1, PIGA, HLA mutations decreased vs. myeloid mutations ASXL1, RUNX1, SETBP1 increased

**Table 5.** Haploidentical Hematopoietic Cell Transplantation in Severe Aplastic Anemia
	DeZern phase 2 single center	DeZern phase 2 multicenter
HCT: hematopoietic cell transplantation; SAA: severe aplastic anemia; BMTCTN: Blood and Marrow Transplant Clinical Trials Network; TBI: total body irradiation; cGVHD: chronic graft-vs-host disease; IQR: interquartile range; ATG: anti-thymocyte globulin; FLU: fludarabine; CY: cyclophosphamide; PTCY: posttransplant cyclophosphamide; GVHD: graft-vs-host disease; CI: confidence interval.
Number	27	31
Year	2016 - 2020	2017 - 2020
Median time from diagnosis to HCT	78 (12 - 249) days	10.8 (4.5 - 109.5) months
Donors/graft source	Haploidentical/bone marrow	Haploidentical/bone marrow
Median age, range	25 (3 - 63) years	24.9 (2.1 - 70.3) years
Conditioning	ATG, FLU, CY, TBI 2 - 4 Gy	ATG, FLU, CY, TBI 2 Gy
GVHD prophylaxis	PTCY, mycophenolate mofetil, tacrolimus	PTCY, mycophenolate mofetil, tacrolimus
Graft failure (GF)	3/7 with TBI 2 Gy; 0/20 with TBI 4 Gy	Primary GF n = 4; Secondary GF n = 1
Cumulative incidence of acute GVHD at day +100	Grade I - II 7%	Grade II 16%
cGVHD	At 3 years mild cGVHD 4%	1-year moderate cGVHD 26%
Overall survival (OS)	3-year OS 92% but with TBI 4 Gy: 3-year OS 100%	1-year OS 81% (95% CI: 62 - 91)
Causes of death	Graft failure with infections (viral)	Graft failure, fungal infection, interstitial pneumonia
Neutrophil engraftment	17 days (range 14 - 88)	17 days (range 1 - 69 days, IQR: 15 - 19)
Day +28 cumulative incidence neutrophil engraftment	96% (95% CI: 87 - 100)	94% (95% CI: 72 - 99)
Platelet engraftment	25.5 days	23 days (range 1 - 49, IQR: 17 - 33)
Day +100 cumulative incidence of platelet transfusion independence	88% (95% CI: 74 - 100)	77% (95% CI: 57 - 89)

Table 5. Haploidentical Hematopoietic Cell Transplantation in Severe Aplastic Anemia

DeZern phase 2 single center

DeZern phase 2 multicenter

Newly diagnosed SAA

Relapsed/refractory SAA (BMTCTN 15-02)

HCT: hematopoietic cell transplantation; SAA: severe aplastic anemia; BMTCTN: Blood and Marrow Transplant Clinical Trials Network; TBI: total body irradiation; cGVHD: chronic graft-vs-host disease; IQR: interquartile range; ATG: anti-thymocyte globulin; FLU: fludarabine; CY: cyclophosphamide; PTCY: posttransplant cyclophosphamide; GVHD: graft-vs-host disease; CI: confidence interval.

Number

Year

2016 - 2020

2017 - 2020

Median time from diagnosis to HCT

78 (12 - 249) days

10.8 (4.5 - 109.5) months

Donors/graft source

Haploidentical/bone marrow

Median age, range

25 (3 - 63) years

24.9 (2.1 - 70.3) years

Conditioning

ATG, FLU, CY, TBI 2 - 4 Gy

ATG, FLU, CY, TBI 2 Gy

GVHD prophylaxis

PTCY, mycophenolate mofetil, tacrolimus

Graft failure (GF)

3/7 with TBI 2 Gy; 0/20 with TBI 4 Gy

Primary GF n = 4; Secondary GF n = 1

Cumulative incidence of acute GVHD at day +100

Grade I - II 7%

Grade II 16%

cGVHD

At 3 years mild cGVHD 4%

1-year moderate cGVHD 26%

Overall survival (OS)

3-year OS 92% but with TBI 4 Gy: 3-year OS 100%

1-year OS 81% (95% CI: 62 - 91)

Causes of death

Graft failure with infections (viral)

Graft failure, fungal infection, interstitial pneumonia

Neutrophil engraftment

17 days (range 14 - 88)

17 days (range 1 - 69 days, IQR: 15 - 19)

Day +28 cumulative incidence neutrophil engraftment

96% (95% CI: 87 - 100)

94% (95% CI: 72 - 99)

Platelet engraftment

25.5 days

23 days (range 1 - 49, IQR: 17 - 33)

Day +100 cumulative incidence of platelet transfusion independence

88% (95% CI: 74 - 100)

77% (95% CI: 57 - 89)

**Table 6.** Future Prospective Studies of Upfront Hematopoietic Cell Transplantation in Newly Diagnosed Severe Aplastic Anemia Patients Without a Matched Sibling Donor
Study	Goal	Age years	Donor	Graft source	Conditioning	GVHD prophylaxis	Primary endpoint
BMTCTN: Blood and Marrow Transplant Clinical Trials Network; hATG: horse anti-thymocyte globulin; CSA: cyclosporine; BM: bone marrow; FLU: fludarabine; CY: cyclophosphamide; TBI: total body irradiation; MTX: methotrexate; PTCY: posttransplant cyclophosphamide; GVHD: graft-vs-host disease.
TransIT BMTCTN 22-02 phase III	235 patients	≤ 25	IST hATG + CSA vs. 10/10 or 9/10 unrelated donor	BM	FLU, CY, ATG, and TBI 2 Gy	CSA and MTX	Time to treatment failure
CUREAA BMTCTN 22-07 phase II	60 patients	> 25	Haploidentical or 10/10, 9/10, or 8/10 unrelated donor	BM	FLU, CY, ATG, and TBI 4 Gy	PTCY, tacrolimus and mycophenolate mofetil	GVHD-failure-free survival at 1 year

Table 6. Future Prospective Studies of Upfront Hematopoietic Cell Transplantation in Newly Diagnosed Severe Aplastic Anemia Patients Without a Matched Sibling Donor

Study

Goal

Age years

Donor

Graft source

Conditioning

GVHD prophylaxis

Primary endpoint

BMTCTN: Blood and Marrow Transplant Clinical Trials Network; hATG: horse anti-thymocyte globulin; CSA: cyclosporine; BM: bone marrow; FLU: fludarabine; CY: cyclophosphamide; TBI: total body irradiation; MTX: methotrexate; PTCY: posttransplant cyclophosphamide; GVHD: graft-vs-host disease.

TransIT BMTCTN 22-02 phase III

235 patients

≤ 25

IST hATG + CSA vs. 10/10 or 9/10 unrelated donor

FLU, CY, ATG, and TBI 2 Gy

CSA and MTX

Time to treatment failure

CUREAA BMTCTN 22-07 phase II

60 patients

> 25

Haploidentical or 10/10, 9/10, or 8/10 unrelated donor

FLU, CY, ATG, and TBI 4 Gy

PTCY, tacrolimus and mycophenolate mofetil

GVHD-failure-free survival at 1 year