HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for chronic myeloid leukemia: Improved outcomes in patients in accelerated phase and blast crisis phase

Figures & data

Table

allo-HSCT	allogeneic hematopoietic stem cell transplantation
AP	accelerated phase
ATG	anti-human thymocyte immunoglobulin
BC	blast crisis
BM	bone marrow
CBT	cord blood transplantation
CML	chronic myeloid leukemia
CMV	cytomegalovirus
CP	chronic phase
CsA	cyclosporin A
DLI	donor lymphocyte infusion
EBMT	European Group for Blood and Marrow Transplantation
FISH	fluorescent in situ hybridization
G-CSF	granulocyte colony-stimulating factor
G-BM	granulocyte colony-stimulating factor primed bone marrow
G-PB	granulocyte colony-stimulating factor mobilized peripheral blood stem cell grafts
GVHD	graft-versus-host disease
GVL	graft-versus-leukemia
HLA	human leukocyte antigen
IBMTR	International Bone Marrow Transplant Registry
IP	idiopathic interstitial pneumonia
LFS	leukemia-free survival
MMF	mycophenolate mofetil
MNC	mononuclear cell
MRD	minimal residual disease
MTX	methotrexate
NIMA	non-inherited maternal antigens
NIPA	non-inherited paternal antigens
OS	overall survival
PBSCs	peripheral blood stem cells
PCR	polymerase chain reaction
TCD	T cell depletion
TRM	transplantation-related mortality

Table I.  Patients’ characteristics.

	Total	Group 1 1 HLA mm	Group 2 2–3 HLA mm	P
No. of patients	93	16	77
Age (years, median and range)
Recipient	29 (9–54)	29 (10–54)	30 (9–51)	0.819
Donor	40 (14–67)	47 (17–65)	40 (14–67)	0.241
Stage of disease at BMT (percentage)				0.913
CP + CP2	65 (69.9%)	11 (68.8%)	54 (70.1%)
AP + BC	28 (30.1%)	5 (31.3%)	23 (29.9%)
ABO compatibility (percentage)				0.555
Matched	60 (64.5%)	12 (75%)	48 (62.3%)
Minor mismatch	18 (19.4%)	2 (12.5%)	16 (20.8%)
Major mismatch	12 (12.9%)	1 (6.3%)	11 (14.3%)
Bidirectional mismatch	3 (3.2%)	1 (6.3%)	2 (2.6%)
Donor-recipient gender match (percentage)				0.017
Male-male	30 (32.3%)	9 (56.3%)	21 (27.3%)
Male-female	16 (17.2%)	0 (0%)	16 (17.2%)
Female-male	33 (35.5%)	6 (37.5%)	27 (35.1%)
Female-female	14 (15.1%)	1 (6.3%)	13 (16.9%)
Donor-recipient relationship (percentage)				0.152
Parent-child	46 (49.5%)	8 (50%)	38 (49.4%)
Sibling-sibling	38 (40.9%)	8 (50%)	30 (39%)
Child-parent	9 (9.7%)	0 (0%)	9 (11.7%)
Gratwohl score (percentage)				0.713
1	3 (3.2%)	1 (6.3%)	2 (2.6%)
2	22 (23.7%)	2 (12.5%)	20 (26%)
3	26 (28%)	6 (37.5%)	20 (26%)
4	23 (24.7%)	3 (18.8%)	20 (26%)
5	11 (11.8%)	2 (12.5%)	9 (11.7%)
6–7	8 (8.6%)	2 (12.5%)	6 (7.8%)

Characteristics of the 93 patients studied. All patient-donor pairs were related and shared one haplotype. Thus they were genotypically identical–-only for one haplotype. HLA mismatch (mm) indicate the number of mismatched HLA-A, B, DR antigens. The data are either numbers of patients or else as indicated in parenthesis. HLA mm = human leukocyte antigen mismatch; BMT = bone marrow transplantation; CP = chronic phase; AP = accelerated phase; BC = blast crisis.

Table II.  Comparison of patients transplanted with HLA class I, class I + II, or class I + II mismatched donors.

	HLA class I	HLA class II	HLA class I and II	P
No. of patients	20	7	66
Age (years, median and range)
Recipient	31 (14–54)	23 (10–41)	29.5 (9–51)	NS
Donor	39 (14–65)	48 (17–55)	40 (14–67)	NS
Stage of disease at transplantation				0.682
CP + CP2	15 (75%)	4 (57.1%)	46 (69.7%)
AP + BC	5 (25%)	3 (42.9%)	20 (30.3%)
Acute GVHD (%)
0–I	15 (75%)	5 (71.4%)	39 (59.1%)	0.392
II–IV	5 (25%)	2 (28.6%)	27 (40.9%)	0.392
III–IV	1 (5%)	1 (14.3%)	16 (24.2%)	0.152
TRM (%)	4 (20%)	1 (14.3%)	12 (18.2%)	0.944
Relapse (%)	2 (10%)	1 (14.3%)	6 (9.1%)	0.906
Survival (%)	15 (75%)	5 (71.4%)	50 (75.8%)	0.968
LFS (%)	14 (70%)	5 (71.4%)	48 (72.7%)	0.971

HLA mismatches indicate the number of mismatched HLA-A, B, DR antigens. HLA class I includes HLA-A, HLA-B, and HLA-A + B; HLA class II stands for HLA-DR; HLA-class I + II includes HLA-A + DR, HLA-B + DR, and HLA-A + B+DR. The results for engraftment, acute GVHD, TRM, relapse, survival, and LFS present probabilities at years determined by the method of Kaplan and Meier. The differences among these three groups were all not significant. HLA = human leukocyte antigen; CP = chronic phase; AP = accelerated phase; BC = blast crisis; GVHD = graft-versus-host disease; TRM = transplantation related mortality; LFS = leukemia-free survival.

Figure 1.  Cumulative incidence of II–IV and III–IV acute graft-versus-host disease (GVHD) after haploidentical transplantation. A: Comparison of the incidence of II–IV acute GVHD between patients with human leukocyte antigen (HLA)-B plus HLA-DR mismatched donors and those without (P=0.011); B: Comparison of the incidence of III–IV acute GVHD between patients with HLA-B plus HLA-DR mismatched donors and those without (P=0.015).

Table III.  Clinical outcome in relation to the number of HLA mismatches.

	Total (n=93)	Group 1: 1 HLA mm (n=16)	Group 2: 2–3 HLA mm (n=77)	P
Acute GVHD
0–I	63.4%	68.8%	62.3%	NS
II–IV	36.6%	31.3%	37.7%	NS
III–IV	19.4%	6.3%	22.1%	NS
TRM
100 d	8.6%	6.3%	9.1%	NS
365 d	18.3%	25v%	16.9%	NS
Relapse
1 years	6.5%	0%	7.8%	NS
4 years	9.7%	6.3%	10.4%	NS
Survival
1 years	77.4%	75%	77.9%	NS
4 years	75.3%	68.8%	76.6%	NS
LFS
1 years	75.3%	75%	75.3%	NS
4 years	72%	68.8%	72.7%	NS

The results are indicated in numbers of patients (and percentages), the data for survival, LFS, relapse, and TRM are probabilities determined by the method of Kaplan and Meier. HLA mm = human leukocyte antigen mismatch; GVHD = graft-versus-host disease; TRM = transplantation related mortality; LFS = leukemia-free survival.

Table IV.  Characteristics of relapsed patients and outcomes.

Number	Stage of disease before transplantation	Therapy using STI before transplantation	Response to STI	States in relapse after transplantation	Post therapy	Clinical outcome
1	CP	STI	No response	Cytogenetic relapse	DLI +STI	DFS
2	CP	STI	No response	Cytogenetic relapse	DLI	Died of infection
3	AP	STI	No response	Cytogenetic relapse	DLI	Died of GVHD
4	AP	STI	No response	Hematological relapse	DLI + STI	Died of GVHD
5	BC	—	—	Hematological relapse	DLI	Died of relapse
6	BC	STI	Response	Cytogenetic relapse	STI	DFS
7	BC	—	—	Hematological relapse	STI	Died of relapse
8	BC	—	—	Hematological relapse	DLI + STI	Died of relapse
9	BC	—	—	Hematological relapse	DLI	Died of relapse

— indicates that patients did not receive the therapy of STI before transplantation.

CP = chronic phase; AP = accelerated phase; BC = blast crisis; STI = imatinib mesylate; DFS = disease free survival; DLI = donor lymphocyte infusion; GVHD = graft-versus-host disease.

Figure 2.  Comparison of overall survival in four groups of patients defined according to the stage of disease (chronic phase (CP) 1, CP2, acute phase (AP), blast crisis (BC)). The best is patients transplanted in CP2, then patients in CP1, AP, and BC. No significant differences were found in our transplant protocol.

Table V.  Multivariate analysis: factors affecting transplantation outcome.

Outcome and factors	RR (95% CI)	P-value
LFS: Time from diagnosis to transplant (≤450 d versus >450 d)	2.783 (1.283–6.035)	0.010
OS: Time from diagnosis to transplant (≤450 d versus >450 d)	2.996 (1.310–6.852)	0.009
TRM: Time from diagnosis to transplant (≤450 d versus >450 d)	3.163 (1.201–8.330)	0.020
Relapse: (AP + BC) versus (CP1 + CP2)	14.467 (1.779–117.672)	0.012
II–IV acute GVHD: HLA-B + DR mismatches versus others	3.146 (1.259–7.859)	0.014
III–IV acute GVHD: HLA-B + DR mismatches versus others	11.208 (1.454–86.402)	0.020

Cox regression analysis on LFS, OS, TRM, relapse, II–IV acute GVHD, and III–IV acute GVHD was performed. Factors included in the models were recipient and donor ages, sex, diagnosis, (AP + BC) versus (CP + CP2), with versus without imatinib before transplantation, EBMT score before transplantation, HLA-B + DR mismatches versus others, dose of CD3⁺ T cell and dose of CD34⁺ cells in the allograft, time from diagnosis to transplant. The final multivariate models were built using a forward stepwise model selection approach.

RR = relative risk; CI = confidence interval; LFS = leukemia-free survival; OS = overall survival; TRM = transplantation related mortality; AP = accelerated phase; BC = blast crisis; CP = chronic phase; HLA = human leukocyte antigen; EBMT = European Group for Blood and Marrow Transplantation.