Abstract

Allogeneic hematopoietic cell transplantation (HCT) from HLA-matched sibling (MS) or unrelated donors (MU) is a well-established treatment for patients with intermediate/high-risk acute myelogenous leukemia (AML) in remission. When HLA-matched donors are not available, however, use of haploidentical family (HF) donors for HCT remains controversial.

Therefore, we performed a prospective study, where patients with AML in complete remission (CR) underwent allogeneic HCT according to the donor priority of MS, MU, or HF donors. Conditioning regimen for MS-HCT was busulfan (3.2 mg/kg • 4 days)-cyclophosphamide (60 mg/kg • 2 days) or, for patients >55 years or with co-morbidity, busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (1.5 mg/kg • 3 days). Patients undergoing MU- or HF-HCT received busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (3 mg/kg • 3 days) (Lee K-H et al; Blood 2011;118:2609-2617; Am J Hematol 2011;86:399-405). Ex-vivo T cell depletion was not performed. GVHD prophylaxis included cyclosporine plus a short course of methotrexate.

Between January 2010 and December 2014, 244 patients enrolled. Of those, 16 patients were excluded from the analysis (12 patients relapsed before HCT; 3 with major protocol violation; and 1 with incomplete data). Of remaining 228 patients, 81 underwent HCT from MS donors, 90 from MU donors, and 57 from HF donors. The donors for MU-HCT were younger and more male-dominant than those for MS- or HF-HCT. The characteristics of patients and their donors were summarized in Table 1.

Table 1.
MS-HCT (n=81)UD-HCT (n=90)HF-HCT (n=57)P*
Median age, yr (range) 48 (19-66) 43 (16-66) 46 (17-69)  
Sex, male/female 37/44 44/46 29/28 0.824 
CR1/CR2 76/5 82/8 47/10 0.098 
Chromosome risk,
low**/intermediate/high/high-monosomal 
6/57/10/5 4/65/16/3 2/40/7/5 0.751 
Donor median age, yr (range) 45 (18-63) 28 (20-45) 29 (15-58)  
Donor age, yr
up to 25
26-45
over 45 
4
41
36 
29
61
19
32
0.000 
Donor sex, male/female 46/35 76/14 36/21 0.000 
Donor relation,
parents/sibling/offspring 
  7/24/26  
HLA allele mismatch/8 (GVH direction), 0/1/2/3/4 81/0/0/0 51/26/10/2/1 0/0/5/22/30 0.000 
Graft, bone marrow/peripheral blood 28/53 0/90 0/57 0.000 
Median nucleated cell count, •108/kg (range) 8.0 (0.9-19.0) 10.8 (4.1-31.4) 10.8 (5.1-19.3)  
Median CD34+ count, •106/kg (range) 4.9 (0.8-18.0) 8.0 (1.4-26.2) 6.4 (2.4-25.7)  
MS-HCT (n=81)UD-HCT (n=90)HF-HCT (n=57)P*
Median age, yr (range) 48 (19-66) 43 (16-66) 46 (17-69)  
Sex, male/female 37/44 44/46 29/28 0.824 
CR1/CR2 76/5 82/8 47/10 0.098 
Chromosome risk,
low**/intermediate/high/high-monosomal 
6/57/10/5 4/65/16/3 2/40/7/5 0.751 
Donor median age, yr (range) 45 (18-63) 28 (20-45) 29 (15-58)  
Donor age, yr
up to 25
26-45
over 45 
4
41
36 
29
61
19
32
0.000 
Donor sex, male/female 46/35 76/14 36/21 0.000 
Donor relation,
parents/sibling/offspring 
  7/24/26  
HLA allele mismatch/8 (GVH direction), 0/1/2/3/4 81/0/0/0 51/26/10/2/1 0/0/5/22/30 0.000 
Graft, bone marrow/peripheral blood 28/53 0/90 0/57 0.000 
Median nucleated cell count, •108/kg (range) 8.0 (0.9-19.0) 10.8 (4.1-31.4) 10.8 (5.1-19.3)  
Median CD34+ count, •106/kg (range) 4.9 (0.8-18.0) 8.0 (1.4-26.2) 6.4 (2.4-25.7)  

*by Chi-square test; **Twelve patients with AML of low-risk chromosomal abnormality included 6 patients in CR2, 3 with c-kit mutation, and 3 with persistent aml1-eto or cbf beta-myh11 after induction chemotherapy.

The median follow-up duration of 164 survivors in the study was 34.7 months (range, 3.7-63.6) after HCT. The donor-group effect on the HCT outcomes was described in Table 2. Patients who underwent MS-HCT showed slightly slower neutrophil engraftment and higher incidence of chronic GVHD. Otherwise, in terms of disease recurrence, NRM, graft failure, EFS, and OS, there was no significant difference according to the donor-type. For AML recurrence, cytogenetic risk was an independent prognostic factors (P =0.003; hazard ratio of low-risk to; intermediate-risk, 1.42; high-risk, 2.53; high-risk with monosomal karyotype, 5.47).

Table 1.
MS-HCT (n=81)UD-HCT (n=90)HF-HCT (n=57)P
Cumulative incidence ( 95% confidence interval)* 
AML recurrence 29% (19-40%) 26% (17-36%) 35% (20-51%) 0.785 
Non-relapse mortality (NRM) 8% (3-16%) 7% (2%-16%) 11% (4-21%) 0.435 
Graft failure 1% (0.1-6%) 6% (2-12%) 5% (1-13%) 0.293 
ANC>500/uL
median days (range) 
100%
13 (9-20) 
99%
12 (10-45) 
98%
12 (6-22) 
0.049 
Platelet>20,000/uL
median days (range) 
99% (86-100%)
14 (0-83) 
97% (88-99%)
13 (0-77) 
96% (83-99%)
14 (0-106) 
0.352 
Grades 2-4 acute graft-versus-host disease (GVHD)  12% (6-21%) 13% (7-21%) 23% (13-34%) 0.176 
Moderate to severe chronic GVHD 39% (28-50%) 22% (13-30%) 23% (13-35%) 0.0452 
4-year survival** 
Event-free (EFS) 63% 69% 54% 0.381 
Overall (OS) 62% 74% 64% 0.077 
MS-HCT (n=81)UD-HCT (n=90)HF-HCT (n=57)P
Cumulative incidence ( 95% confidence interval)* 
AML recurrence 29% (19-40%) 26% (17-36%) 35% (20-51%) 0.785 
Non-relapse mortality (NRM) 8% (3-16%) 7% (2%-16%) 11% (4-21%) 0.435 
Graft failure 1% (0.1-6%) 6% (2-12%) 5% (1-13%) 0.293 
ANC>500/uL
median days (range) 
100%
13 (9-20) 
99%
12 (10-45) 
98%
12 (6-22) 
0.049 
Platelet>20,000/uL
median days (range) 
99% (86-100%)
14 (0-83) 
97% (88-99%)
13 (0-77) 
96% (83-99%)
14 (0-106) 
0.352 
Grades 2-4 acute graft-versus-host disease (GVHD)  12% (6-21%) 13% (7-21%) 23% (13-34%) 0.176 
Moderate to severe chronic GVHD 39% (28-50%) 22% (13-30%) 23% (13-35%) 0.0452 
4-year survival** 
Event-free (EFS) 63% 69% 54% 0.381 
Overall (OS) 62% 74% 64% 0.077 

*compared by Gray's method; **compared by log-rank test

Our study showed that, despite heterogeneity of baseline donor characteristics (age and sex), conditioning regimen, and graft source (bone marrow vs. peripheral blood), overall post-transplant outcomes were similar among recipients from MS-, MU-, and HF-donors. Therefore, for patients with AML in CR but without an HLA-matched donor available, HCT from a haploidentical family member may be considered.

Disclosures

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.