Donor selection in T-cell-replete haploidentical-related donor peripheral blood stem cell transplantation

doi:10.21203/rs.3.rs-4963596/v1

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Donor selection in T-cell-replete haploidentical-related donor peripheral blood stem cell transplantation

https://doi.org/10.21203/rs.3.rs-4963596/v1

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The effects of donor characteristics on outcomes after T-cell-replete (TCR) haploidentical-related donor peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) or low-dose antithymocyte globulin (ATG) remain unclear. We evaluated the impact in 1,677 patients who received a PTCy protocol (PTCy-haplo; n = 1,107) or low-dose ATG protocol (ATG-haplo; n = 570). A low CD34⁺ cell dose (<4 ×10^6/kg) was the only donor characteristic associated with worse overall survival (OS) after PTCy-haplo (adjusted hazard ratios [aHR] = 1.49, P = 0.008), whereas increased donor age by decade (aHR = 1.12, P = 0.008) and a large number of human leukocyte antigen mismatches (aHR = 1.46, P = 0.010) were associated with worse OS after ATG-haplo. Donor age increased the risk of grade II–IV acute graft-versus-host disease (GVHD) only after ATG-haplo (HR: 1.14, P = 0.018), whereas it increased the risk of grade III–IV acute GVHD both after PTCy-haplo (HR: 1.32, P = 0.009) and ATG-haplo (HR: 1.22, P = 0.006). Offspring donors had better relapse-free survival and GRFS than sibling donors after ATG-haplo. Our data suggest a comprehensive donor selection hierarchy after TCR haploidentical related-donor PBSCT with PTCy or low-dose ATG.

Health sciences/Medical research

Biological sciences/Cancer/Haematological cancer

Human leukocyte antigen (HLA)-haploidentical family donors are recognized as important sources for patients with hematological diseases requiring allogeneic hematopoietic stem cell transplantation (HSCT).^1–4 The likelihood of identifying an HLA-haploidentical donor in a family is over 95%, and the average number of such donors per patient is more than two.⁵ This is primarily the result of successful development of graft-versus-host disease (GVHD) prophylaxis to overcome the alloreactivity caused by HLA mismatch.⁶

HLA-haploidentical HSCT (haplo-HSCT) has gained global adoption through T-cell-replete (TCR) approaches, including post-transplantation cyclophosphamide (PTCy)- or antithymocyte globulin (ATG)-based protocols. Haplo-HSCT using PTCy (PTCy-haplo) was initially developed in the setting of bone marrow (BM) transplant following reduced-intensity conditioning (RIC).^7,8 Recently, PTCy-haplo procedure has been modified and updated using peripheral blood stem cells (PBSCs)^9,10 or myeloablative conditionings (MAC).^11,12 On the other hand, ATG-based haplo-HSCT (ATG-haplo) was initially developed with high dose of ATG, and “GIAC” (G-CSF mobilization, intensive immunosuppression, ATG and combination of BM and PBSCs) protocol by Chinese group has shown promising results.^13–16 Recently, low-dose ATG has also been shown to be an effective GVHD prophylaxis in the haplo-HSCT setting for attenuation of GVHD without increasing ATG toxicity.^17–23

One of the key issues in TCR-haplo-HSCT settings is finding the best donor in these recently matured practices, because the impact of donor characteristics can change over time. In this study, we investigated the effect of donor characteristics on outcomes after PTCy-haplo peripheral blood stem cell transplantation (PBSCT) and low-dose ATG-haplo PBSCT. First, donor characteristics were comprehensively analyzed, and the impact of donor-recipient kinship (offspring vs sibling, parents vs siblings, and first-degree [FD] vs non-first-degree [NFD]) was analyzed after accounting for confounding factors against recipient age.

Study patients

We included 1,786 adult patients with hematological malignancies who received PTCy-haplo (1,149 patients) or ATG-haplo (637 patients) PBSCT. All patients were enrolled in the Transplant Registry Unified Management Program (TRUMP) 2 of the Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT) between 2013 and 2020. Among the 6,252 patients who received their first related donor HSCT and were enrolled in TRUMP 2, we excluded 3,754 patients who underwent HLA-matched HSCT and five patients who lacked HLA data. Patients who received GVHD prophylaxis with anti-T lymphoglobulin (ATLG), alemtuzumab, ATG other than thymoglobulin, high-dose thymoglobulin (> 10 mg/kg), or PTCy plus thymoglobulin were excluded. We also excluded 344 patients who received GVHD prophylaxis using calcineurin inhibitors and methotrexate with or without mycophenolate mofetil. Five recipients whose age difference from their offspring was less than 15 years were excluded from the study. Finally, 109 cases that used stem cell sources from BM were excluded (Supplementary Fig. 1).

The transplant data were obtained from the JDCHCT registry database. The MAC and RIC were defined as previously described.²⁴ Standard-risk diseases were defined as acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) in complete remission (CR), myelodysplastic syndrome (MDS) with refractory anemia or refractory anemia with ringed sideroblasts, chronic myelogenous leukemia in the chronic and accelerated phases, adult T-cell leukemia in CR, lymphoma in complete or partial remission, and multiple myeloma in CR; all other conditions were considered high-risk diseases, as in previous studies.^22,25,26 HLA compatibility was determined at HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci between recipients and donors using standard serologic techniques and high-resolution DNA typing. All recipients provided informed consent before registration in TRUMP 2. This study was approved by the Data Management Committee of the JDCHCT and the Ethics Committee of Kyoto University and was conducted in accordance with the Declaration of Helsinki.

Endpoints and statistical analysis

The primary endpoint of this study was the impact of donor characteristics on overall survival (OS) in PTCy-haplo and ATG-haplo patients. The following secondary endpoints were evaluated: relapse-free survival (RFS), GVHD-free relapse-free survival (GRFS), relapse and non-relapse mortality (NRM), grade II–IV acute GVHD, grade III–IV acute GVHD, chronic GVHD, extensive chronic GVHD. The diagnosis and grading of acute and chronic GVHD were performed according to previous reports.^27,28

Donors, recipients, diseases, and transplant characteristics were compared between groups using the chi-square test or Fisher’s exact test for categorical variables and the Kruskal–Wallis test for continuous variables. The impact of donor characteristics on the outcomes of interest was evaluated using Cox proportional hazards models or the Fine-Gray sub-distribution hazard model.²⁹ The endpoints are presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). The adjusted covariates included donor age, ABO compatibility (match, major mismatch, major minor mismatch, or minor mismatch), sex compatibility (female to male, male to male, female to female, or male to female), cytomegalovirus (CMV) serostatus (positive donor for negative recipient, negative donor for negative recipient, positive donor for positive recipient, or negative donor for positive recipient), HLA antigen mismatch (0–1 or 2–3), and infused CD34 + cell dose (low, intermediate, or high) as donor factors. For sex compatibility and cytomegalovirus (CMV) serostatus, multivariate analyses were performed twice with different references (female recipient or male recipient, and CMV negative recipient or CMV positive recipient) in the four groups. The following were also included as non-donor covariates: recipient age, disease (myeloid or lymphoid), ECOG performance status (PS) (0–1 or > 1), disease status (standard or high-risk), and conditioning regimen intensity (MAC or RIC). Kinship was not included as a covariate because it was confounded by donor or recipient age. All tests were two-sided, and P values < 0.05 were considered statistically significant.

The CD34⁺ cell dose was treated as a categorical variable (low: <4 ×10^6/kg, middle: 4–7 ×10^6/kg, or high: > 7 ×10^6/kg) because the effect of the CD34⁺ cell dose on the relative death risk after PTCy-haplo was not linear in spline terms in the Cox model (Supplementary Fig. 2A, B). Lower cut-off value was set at 4 ×10^6/kg based on the median number of infused CD34⁺ cell dose (4.23×10^6/kg) (Supplementary Fig. 2C). A higher cut-off value was set at 7 ×10^6/kg because it was the boundary point at which the slope of the spline terms changed from negative to positive after PTCy-haplo (Supplementary Fig. 2A).

Regarding the effect of donor or recipient age on OS, we also applied spline terms to a Cox model to investigate whether the association was linear. The relative risk of death was calculated using the youngest age of the donor or recipient as the comparison standard. All statistical analyses were performed using R (version 4.2.2; R Development Core Team, Vienna, Austria) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan).

Inverse probability treatment weighting and propensity score matching

Owing to the relationship between recipient age and donor-recipient kinship (Fig. 1A), we performed separate analyses for recipients aged ≥ 40 and < 40 years when assessing the impact of kinship on transplant outcomes. For recipients aged ≥ 40 years old, offspring and sibling donors were compared according to PTCY-haplo and ATG-haplo, respectively. For recipients aged < 40 years, we first compared parent and sibling donors and then compared maternal and paternal donors according to PTCY-haplo and ATG-haplo, respectively. We utilized inverse probability treatment weight (IPTW) analysis to reduce the effect of confounding factors and secured numbers for the analysis.³⁰ First, we calculated the propensity score (PS) using a logistic regression model. Covariates that may influence donor selection and outcomes were selected clinically. These included the recipient age, ABO compatibility, sex compatibility, CMV antibody status, HLA antigen mismatch, infused CD34 + cell dose, disease, PS, disease status, and conditioning regimen intensity. Donor age was not included because it was considered a confounding factor for donor-recipient kinship (Fig. 1A). Second, we calculated the weights to adjust for confounding factors in the Cox regression and Fine and Gray analyses. Finally, a comparative analysis of interest was performed individually for each completed dataset using IPTW analysis.

Finally, we performed a subgroup analysis to compare transplant outcomes between (FD) donors and non-first-degree (NFD) related donors. PS matching was performed to minimize pre-transplant imbalances between the NFD and FD cohorts.³¹ Because of the small number of NFD-related donors (n = 46, 2.7%), we compared FD and NFD donors without stratifying them into PTCy-haplo and ATG-haplo groups in a PS-matched cohort. Logistic regression was used to calculate the PS based on the same variables as above in addition to the TCR approach (PTCy-haplo or ATG-haplo). A 1:1 caliper matching was performed using the nearest neighbor matching method with a fixed caliper width of 0.2 of the standard deviation of the PS. The probabilities of OS were calculated using the Kaplan–Meier estimate, and the incidences of grade II–IV acute and chronic GVHD were estimated utilizing the cumulative incidence curve.

Transplant characteristics

We enrolled 1,677 patients in this study. Among these patients, 1,107 received PTCy-haplo PBSCT and 570 received ATG-haplo PBSCT. The donor, recipient, and other transplant characteristics are shown in Table 1. The median donor age was 34 years (range: 11 to 74 years), and the median recipient age was 55 years (range: 16 to 75 years). Six hundred six recipients (36.1%) were female, and 1,071 (63.9%) were male. The most common diagnosis was AML (41.1%), followed by ALL (13.9%) and MDS (11.7%). The CMV serostatus was CMV-positive donors (72.7%) and CMV-positive recipients (87.7%). The percentages of CMV antigenemia and infection according to donor/recipient CMV serostatus are shown in Supplementary Fig. 3. Donor-recipient kinship included parent in 8.9%, sibling in 32.0%, offspring in 56.4%, and NFD relative in 2.7% of cases. The median total dose of PTCy in the PTCy-haplo cohort was 100 mg/kg (40–120 mg/kg) on days 3 and 4 (or 5). The median total ATG dose in the ATG-haplo cohort was 2.5 (0.50–10.0) mg/kg. Approximately 25 PTCy-haplo recipients and 28 ATG-haplo recipients harbored donor-specific HLA antibodies (DSAs).

Table 1

Patient characteristics.
Variable	PTCy-haplo (n = 1,107)	ATG-haplo (n = 570)	P-value
Donor age			0.414
Median, range	34 (14–67)	34.5 (11–74)
Recipient age			< 0.001
Median, range	56 (16–75)	53 (16–72)
Recipient sex			0.520
Female/Male	394 (35.6)/713 (64.4)	212 (37.2)/338 (62.8)
Sex compatibility			0.438
Female to male	286 (25.8)	160 (20.1)
Male to male	427 (38.6)	198 (34.7)
Female to female	166 (15.0)	85 (14.9)
Male to female	228 (20.6)	127 (22.3)
Diagnosis			NA
AML/ALL	419 (37.9)/146 (13.2)	270 (47.4)/87 (15.3)
MDS	157 (14.2)	40 (7.0)
HL/NHL	11 (1.0)/201 (18.2)	5 (0.9)/103 (18.1)
ATL	100 (9.8)	21 (3.7)
CML/CLL	21 (1.9)/1 (0.1)	12 (2.1)/1 (0.2)
Others*	51 (4.6)	29 (5.3)
ECOG PS			< 0.001
0–1/>1	1014 (91.6)/93 (8.4)	466 (81.8)/104 (18.2)
Disease risk			< 0.001
Standard/High	572 (51.7)/498 (45.0)	166 (29.1)/397 (69.6)
Missing	7 (1.2)	7 (1.2)
ABO			0.042
Match	632 (57.1)	314 (55.1)
Major mismatch	193 (17.4)	130 (22.8)
Major minor mismatch	69 (6.2)	26 (4.6)
Minor mismatch	213 (19.2)	100 (17.5)
CMV serostatus			0.022
Donor (+), Recipient (-)	64 (5.8)	42 (7.4)
Donor (-), Recipient (-)	69 (6.2)	16 (2.8)
Donor (+), Recipient (+)	669 (60.4)	360 (63.2)
Donor (-), Recipient (+)	229 (22.2)	112 (21.1)
Missing	76 (6.9)	40 (7.0)
Conditioning intensity			< 0.001
Reduced intensity	660 (59.6)	406 (71.2)
Myeloablative	447 (40.4)	164 (28.8)
Donor-recipient kinship			NA
Mother/Father	46 (4.2)/35 (3.2)	39 (6.8)/29 (5.1)
Sister/Brother	156 (14.1)/190 (17.2)	88 (15.4)/103 (10.1)
Daughter/Son	243 (22.0)/418 (37.6)	108 (18.9)/178 (31.2)
Non-first degree	21 (1.9)	25 (4.4)
HLA mismatch (A/B/DR antigen)			< 0.001
0/1	11 (1.0)/69 (6.2)	13 (2.3)/105 (18.4)
2/3	386 (34.9)/641 (57.9)	195 (34.2)/257 (45.1)
HLA mismatch (A/B/C/DR genotype)			< 0.001
1/2	12 (1.1)/51 (4.6)	52 (9.1)/51 (8.9)
3/4	303 (27.4)/658 (59.4)	144 (25.3)/233 (40.9)
Missing	83 (7.5)	90 (15.8)
CD34⁺ cells of PBSCs			0.025
Median, range (×10⁶/kg)	4.44 (0.47–12.6)	3.92 (0.43–12.9)
Donor-specific antigens			< 0.001
Positive/Negative	25 (2.3)/1022 (92.3)	28 (4.9)/490 (86.0)
Missing	60 (5.4)	52 (9.1)
Categorical variables are summarized as counts and percentages.
PTCy posttransplant cyclophosphamide, ATG antithymocyte globulin, AML acute myeloid leukemia, ALL acute lymphoid leukemia, MDS Myeloid dysplasia syndrome, HL Hodgkin lymphoma, NHL non-Hodgkin lymphoma, CML chronic myeloid leukemia, CLL chronic lymphoid leukemia, ECOG PS Eastern Cooperative Oncology Group performance status, CMV cytomegalovirus, HLA human leukocyte antigen, PBSCs peripheral blood stem cells.
*Others include multiple myeloma, myeloproliferative neoplasm, and other leukemia.

The donor/recipient characteristics based on age are shown in Fig. 1. Younger recipients had either parents or siblings as potential donors, while older recipients had either siblings or offspring as potential donors (Fig. 1A). The plot of the number of CD34⁺ cells showed an irrelevant distribution (Fig. 1B). The plot of donor/recipient CMV serostatus showed more CMV-negative donors among the CMV-positive recipients when the donor was young and the recipient was older (Fig. 1C).

OS, RFS, and GRFS

Regarding the primary endpoint, a multivariate analysis revealed that low CD34⁺ cell dose was the only donor characteristic that had a negative impact on OS after PTCy-haplo (aHR = 1.49, 95% CI = 1.11–2.00, P = 0.008), whereas increased donor age by decade (aHR = 1.12, 95% CI = 1.03–1.22, P = 0.008) and a larger number of HLA antigen mismatch (aHR = 1.46, 95% CI = 1.10–1.95, P = 0.010) had a negative impact on OS after ATG-haplo (Table 2). Figure 2 shows the relative death risk of donor or recipient age according to spline terms in a Cox model. There was no significant correlation between donor age and death risk in the PTCy-haplo cohort (Fig. 2A); however, there was a linear correlation in the ATG-haplo cohort (Fig. 2B). Furthermore, the risk of death gradually increased around the recipient age of 40 years in the PTCy-haplo group. (Fig. 2C), whereas the risk increased consistently across all ages in the ATG-haplo group (Fig. 2D).

Table 2

Hazard ratios of donor characteristics for main outcomes through multivariable analysis.
	Overall survival						Relapse-free survival
	PTCy-haplo			ATG-haplo			PTCy-haplo			ATG-haplo
Variable	HR	95% CI	P-value	HR	95% CI	P-value	HR	95%CI	P-value	HR	95% CI	P-value
Donor age
per 10 year-increase	1.00	0.91–1.10	0.962	1.12	1.03–1.22	0.008	0.95	0.87–1.04	0.274	1.12	1.03–1.21	0.012
Sex compatibility (Female donor vs male donor)
for male recipient	1.11	0.87–1.42	0.395	1.25	0.96–1.63	0.101	1.08	0.86–1.36	0.521	1.28	0.91–1.53	0.221
for female recipient	1.23	0.86–1.75	0.266	1.02	0.72–1.45	0.899	0.98	0.71–1.36	0.896	0.98	0.70–1.37	0.918
ABO compatibility
major mismatch vs match	0.93	0.71–1.23	0.623	1.22	0.95–1.57	0.123	1.06	0.83–1.35	0.641	1.23	0.96–1.57	0.096
major minor mismatch vs match	0.93	0.60–1.42	0.723	0.91	0.54–1.56	0.742	0.98	0.66–1.45	0.915	0.77	0.45–1.31	0.332
minor mismatch vs match	1.05	0.81–1.36	0.697	1.08	0.81–1.44	0.608	1.05	0.82–1.34	0.691	1.08	0.82–1.43	0.583
CMV serostatus (positive donor vs negative donor)
for CMV negative recipient	0.94	0.52–1.71	0.846	1.85	0.75–4.56	0.183	0.74	0.43–1.28	0.283	2.28	0.93–5.60	0.073
for CMV positive recipient	1.00	0.78–1.27	0.983	0.90	0.70–1.16	0.423	1.09	0.87–1.37	0.439	0.84	0.66–1.08	0.173
HLA antigen compatibility
2–3 vs 0–1 mismatch	1.20	0.78–1.84	0.398	1.46	1.10–1.95	0.010	1.13	0.79–1.63	0.487	1.31	0.99–1.73	0.057
Number of CD34 + PBSCs infused (×10^6/kg)
< 4 vs 4–7	1.49	1.11-2.00	0.008	0.90	0.79–1.18	0.446	1.41	1.08–1.86	0.013	0.92	0.71–1.20	0.550
≧ 7 vs 4–7	1.31	0.84–2.04	0.240	0.97	0.64–1.48	0.900	1.23	0.83–1.83	0.305	0.87	0.58–1.30	0.491
The hazard ratios of donor characteristics according to the PTCy-haplo and ATG-haplo are provided. The other variables included for adjustment were disease, performance status, disease status, and conditioning regimen intensity. Analyses were performed using a Cox proportional hazards model.
PTCy posttransplant cyclophosphamide, ATG antithymocyte globulin, HR hazard ratio, CI confidence interval, PBSCs peripheral blood stem cells, CMV cytomegalovirus, HLA human leukocyte antigen.

Regarding RFS, low CD34⁺ cell dose was the only donor characteristic that had a negative impact after PTCy-haplo (aHR = 1.41, 95% CI = 1.08–1.86, P = 0.013), whereas increased donor age by decade was the only donor characteristic that had a negative impact after ATG-haplo (aHR = 1.12, 95% CI = 1.03–1.21, P = 0.012) (Table 2).

Regarding GRFS, none of donor characteristics had a negative impact after PTCy-haplo, whereas increased donor age by decade (aHR = 1.09, 95% CI = 1.00–1.18, P = 0.040) and CMV-positive donor for CMV-negative recipient (compared to CMV-negative donor for CMV-negative recipient; aHR = 3.56, 95% CI = 1.48–8.58, P = 0.005) had a negative impact after ATG-haplo. In addition, CMV-positive donor for CMV-positive recipient had better GRFS compared to CMV-negative donor for CMV-positive recipient after ATG-haplo (aHR = 0.75, 95% CI = 0.59–0.95, P = 0.019) (Supplementary Table 1).

GVHD

Regarding acute GVHD, increased donor age by decade increased the risk of grade II–IV acute GVHD only after ATG-haplo (aHR = 1.14, 95% CI = 1.02–1.28, P = 0.018), not after PTCy-haplo (aHR = 1.08, 95% CI = 0.97–1.20, P = 0.170) (Table 3). No other donor characteristics increased the risk of grade II–IV acute GVHD after PTCy-haplo and ATG-haplo (Table 3). Increased donor age was a risk factor of grade III–IV acute GVHD both after PTCy-haplo (aHR = 1.32, 95% CI = 1.07–1.63, P = 0.009) and ATG-haplo (aHR = 1.22, 95% CI = 1.06–1.41, P = 0.006) (Supplementary Table 2). In addition, high CD34⁺ cell dose was a risk factor for grade III–IV acute GVHD after ATG-haplo (aHR = 2.04, 95% CI = 1.12–3.73, P = 0.020) (Supplementary Table 2).

Table 3

Hazard ratios of donor characteristics for GVHD occurrence through multivariable analysis.
	Grade II–IV acute GVHD						Chronic GVHD
	PTCy-haplo			ATG-haplo			PTCy-haplo			ATG-haplo
Variable	HR	95% CI	P-value	HR	95% CI	P-value	HR	95%CI	P-value	HR	95% CI	P-value
Donor age
per 10 year-increase	1.08	0.97–1.20	0.170	1.14	1.02–1.28	0.018	1.10	0.98–1.23	0.120	0.95	0.80–1.12	0.510
Sex compatibility (Female donor vs male donor)
for male recipient	1.12	0.83–1.52	0.440	1.01	0.72–1.42	0.960	1.31	0.94–1.84	0.110	0.89	0.54–1.48	0.660
for female recipient	1.12	0.75–1.68	0.580	0.71	0.43–1.16	0.170	0.67	0.39–1.15	0.140	0.79	0.42–1.49	0.460
ABO compatibility
major mismatch vs match	0.96	0.70–1.31	0.790	0.88	0.63–1.24	0.490	1.01	0.69–1.48	0.950	0.90	0.56–1.45	0.670
major minor mismatch vs match	0.64	0.36–1.14	0.130	0.94	0.49–1.78	0.840	1.23	0.74–2.03	0.430	1.02	0.39–2.66	0.970
minor mismatch vs match	0.94	0.69–1.28	0.700	1.38	0.95-2.00	0.091	0.90	0.60–1.34	0.600	0.71	0.41–1.23	0.220
CMV serostatus (positive donor vs negative donor)
for CMV negative recipient	1.10	0.55–2.22	0.790	0.45	0.18–1.08	0.073	0.63	0.29–1.35	0.230	1.25	0.38–4.16	0.720
for CMV positive recipient	1.12	0.83–1.52	0.460	0.90	0.63–1.23	0.560	0.91	0.64–1.30	0.620	0.98	0.61–1.59	0.950
HLA antigen compatibility
2–3 vs 0–1 mismatch	1.37	0.83–2.26	0.220	1.17	0.83–1.64	0.360	1.25	0.68–2.29	0.480	1.19	0.70–2.02	0.510
Number of CD34 + PBSCs infused (×10^6/kg)
< 4 vs 4–7	1.12	0.79–1.61	0.520	0.99	0.70–1.38	0.930	0.81	0.53–1.24	0.340	1.10	0.44–2.73	0.840
≧ 7 vs 4–7	0.79	0.46–1.34	0.380	1.43	0.86–2.37	0.170	0.74	0.41–1.35	0.330	1.77	1.03–3.04	0.037
The hazard ratios of donor characteristics according to the PTCy-haplo and ATG-haplo are provided. The other variables included for adjustment were disease, performance status, disease status, and conditioning regimen intensity. The analyses were performed using the Fine and Gray models.
GVHD graft-versus-host disease, PTCy posttransplant cyclophosphamide, ATG antithymocyte globulin, HR hazard ratio, CI confidence interval, CMV cytomegalovirus, HLA human leukocyte antigen.

Regarding chronic GVHD, none of the donor characteristics increased the risk of chronic GVHD after PTCy-haplo, whereas high CD34⁺ cell dose increased the risk of chronic GVHD after ATG-haplo (aHR = 1.77, 95% CI = 1.03–3.04, P = 0.037) (Table 3). None of the donor characteristics increased the risk of extensive chronic GVHD after PTCy-haplo and ATG-haplo (Supplementary Table 2).

Relapse and NRM

CMV-positive donors for CMV-positive recipients showed higher risk of relapse compared to CMV-negative donors for CMV-positive recipients only after PTCy-haplo (aHR = 1.39, 95% CI = 1.03–1.87, P = 0.031) (Supplementary Table 3). Low CD34⁺ cell dose tended to increase the risk of relapse only after PYCy-haplo (aHR = 1.37, 95% CI = 0.99–1.92, P = 0.061).

CMV-positive donors for CMV-positive recipients tended to reduce the risk of NRM compared to CMV-negative donors for CMV-positive recipients only after PTCy-haplo (aHR = 0.71, 95%CI = 0.50-1.00, P = 0.052). A larger number of HLA antigen mismatch (aHR = 1.79, 95% CI = 1.12–2.85, P = 0.015) increased the risk of NRM only after ATG-haplo (Supplementary Table 3).

Impact of kinship

Offspring vs siblings

Regarding PTCy-haplo, we did not detect any difference in outcomes between offspring and sibling donors (OS; aHR = 0.81, P = 0.313, RFS; aHR = 0.93, P = 0.723, GRFS; aHR = 0.77, P = 0.135) (Table 4). Regarding ATG-haplo, offspring donors were associated with better RFS (aHR = 0.62, 95% CI = 0.43–0.90, P = 0.010) and GRFS (aHR = 0.59, 95% CI = 0.42–0.83, P = 0.003) compared to sibling donors (Table 4).

Table 4

Hazard ratios of donor-recipient kinship for transplant outcomes through inverse probability of treatment weighting analysis.
	Offspring vs Siblings (recipient age > 40 years)						Parent vs Siblings (recipient age ≦ 40 years)
	PTCy-haplo			ATG-haplo			PTCy-haplo			ATG-haplo
Variable	HR	95% CI	P-value	HR	95% CI	P-value	HR	95% CI	P-value	HR	95% CI	P-value
OS	0.81	0.53–1.22	0.313	0.72	0.46–1.11	0.133	1.37	0.68–2.72	0.377	0.91	0.56–1.49	0.714
RFS	0.93	0.62–1.40	0.723	0.62	0.43–0.90	0.010	1.30	0.72–2.37	0.383	1.03	0.62–1.74	0.900
GRFS	0.77	0.55–1.08	0.135	0.59	0.42–0.83	0.003	1.36	0.81–2.27	0.248	0.91	0.57–1.45	0.704
Relapse	0.80	0.42–1.52	0.327	0.69	0.32–1.47	0.339	1.58	0.72–3.49	0.253	1.03	0.46–2.32	0.942
NRM	1.04	0.54–2.02	0.901	0.70	0.33–1.47	0.349	0.93	0.34–2.56	0.886	1.13	0.49–2.62	0.778
Grade II–IV acute GVHD	0.92	0.55–1.54	0.763	0.73	0.38–1.39	0.341	1.36	0.68–2.72	0.386	0.87	0.45–1.72	0.697
Grade III–IV acute GVHD	0.74	0.29–1.89	0.524	0.61	0.27–1.41	0.250	1.33	0.48–3.71	0.580	1.51	0.64–3.58	0.350
Chronic GVHD	1.06	0.62–1.80	0.836	0.59	0.21–1.64	0.312	0.52	0.26–1.04	0.063	0.62	0.24–1.59	0.481
Extensive chronic GVHD	1.10	0.64–1.88	0.736	0.40	0.413–1.17	0.551	0.47	0.16–1.45	0.159	0.44	0.15–1.27	0.127
The hazard ratios of offspring donors for each transplant outcome was compared with those of sibling donors in recipients aged > 40 years. The hazard ratios of parent donors for each transplant outcome was compared with those of sibling donors in recipients aged < 40 years. The covariates used to calculate the propensity score were recipient age, ABO compatibility, sex compatibility, CMV serostatus, HLA antigen mismatch, CD34⁺ cell count, disease, performance status, disease status, and conditioning regimen intensity.
PTCy posttransplant cyclophosphamide, ATG antithymocyte globulin, HR hazard ratio, CI confidence interval, OS overall survival, RFS relapse-free survival, GRFS graft-versus-host disease-free relapse-free survival, NRM nonrelapse mortality, GVHD graft-versus-host disease.

Table 5

Proposed donor selection in T-cell-replete haploidentical related donor PBSCT.
PTCy-haplo	ATG-haplo
・CD34⁺ number (> 4 ×10⁶/kg) (OS and RFS) ・Younger donor over older donor (acute GVHD)	・Younger donor over older donor (OS, RFS and GRFS) ・Less HLA mismatched donor (OS) ・Offspring donor over sibling donor (RFS and GRFS) ・CMV negative donor for CMV negative recipient (GRFS) ・CMV positive donor for CMV positive recipient (GRFS) ・CD34⁺ number (< 7 ×10⁶/kg) (chronic GVHD)
The terms "Parent or Sibling", "Maternal or Paternal", and "First degree or Non-first degree" were not issues in this study
Outcomes significantly influenced are listed in parentheses.
PTCy posttransplant cyclophosphamide, ATG antithymocyte globulin, OS overall survival, RFS relapse-free survival, GRFS graft-versus-host disease-free relapse-free survival, GVHD acute graft-versus-host disease, HLA human leukocyte antigen, CMV cytomegalovirus.

Parent vs siblings

Regarding PTCy-haplo, we did not detect any differences in outcomes between parent and sibling donors (OS; aHR = 1.37, P = 0.377, RFS; aHR = 1.30, P = 0.383, GRFS; aHR = 1.36, P = 0.248) (Table 4). Similarly, for ATG-haplo, no significant differences in outcomes were observed between parent and sibling donors (OS; aHR = 0.91, P = 0.714, RFS; aHR = 1.03, P = 0.900, GRFS; aHR = 0.91, P = 0.704) (Table 4).

Maternal or Paternal

Regarding PTCy-haplo, there were no significant differences in outcomes between maternal and paternal donor transplants (OS; aHR = 1.30, P = 0.526, RFS; aHR = 1.40, P = 0.388, GRFS; aHR = 1.23, P = 0.547) (Supplementary Table 4). Similarly, regarding ATG-haplo, there were no significant differences in outcomes between maternal and paternal donor transplants (OS; aHR = 1.95, P = 0.108, RFS; aHR = 1.28, P = 0.509, GRFS; aHR = 1.41, P = 0.336) (Supplementary Table 4).

First-degree vs Non-first-degree

After PS matching, 45 recipients were stratified into FD and NFD cohorts. The NFD donors consisted of 23 cousins, 18 nephews/nieces, two half-siblings, and two uncles/aunts. The patient characteristics after PS matching are shown in Supplementary Table 5. There were no significant differences in the characteristics of the recipients, diseases, or transplant procedures. The 2-year OS was 45.5% (95% CI: 29.6–60.0%) in the FD cohort and 34.0% (95% CI: 19.8–48.7%) in the NFD cohort (P = 0.468) (Fig. 4A). The 100-day cumulative incidence of Grade II–IV acute GVHD was 37.8% (95% CI: 23.7–51.8%) in the FD cohort and 40.0% (95% CI: 25.6–54.0%) in the NFD cohort (P = 0.830) (Fig. 4B). The 2-year cumulative incidence of chronic GVHD was 24.9% (95% CI: 11.5–40.9%) in the FD cohort and 21.9% (95% CI: 10.0–36.7%) in the NFD cohort (P = 0.560) (Fig. 4C). The HR of each transplant outcome in the NFD cohort compared with that in the FD cohort is shown in Supplementary Table 6. There were no significant differences in OS (HR = 1.22, P = 0.468), RFS (HR = 0.95, P = 0.852), GRFS (HR = 1.06, P = 0.816), relapse (HR = 1.08, P = 0.810), NRM (HR = 1.00, P = 0.990), grade II–IV acute GVHD (HR = 1.07, P = 0.830), grade III–IV acute GVHD (HR = 0.98, P = 0.960), chronic GVHD (HR = 0.76, P = 0.570), or extensive chronic GVHD (HR = 0.97, P = 0.960) between FD and NFD transplant (Supplementary Table 6).

Our largest dataset comprehensively investigated the effect of donor characteristics on outcomes after TCR-haplo PBSCT with PTCy or low-dose ATG. We found that a low CD34⁺ cell dose was associated with poor OS after PTCy-haplo, whereas donor age, CMV-positive donors for CMV-negative recipients, and a larger number of HLA antigen mismatches were associated with poor OS after ATG-haplo. We provide foundational data for optimal donor choices in TCR-haplo PBSCT.

Several conflicting results have been reported regarding the effects of donor age after PTCy-haplo or ATG-haplo HSCT. Consistent with previous reports, we observed no impact of donor age on OS after PTCy-haplo,^32–34 whereas it had a negative effect on OS after ATG-haplo. When focusing on older recipients, some reports have suggested that increased donor age is associated with inferior OS.^35,36 Therefore, we checked the impact of donor age in spline terms in a Cox model using recipient age as one of the covariates. Increased donor age was not associated with the risk of death across all donor ages after PTCy-haplo, whereas there was a linear correlation after ATG-haplo. Our findings may differ from those reported by DeZern et al. who demonstrated that increasing donor age by decade was associated with poorer OS regardless of recipient age after PTCy-haplo.³⁷ The discrepancy may be attributed to the different donor sources (only PBSCs in our study) and disease entities (AML over B-cell lymphoma in our study) between our study and the previous report. However, consistent with previous findings,^38,39 increased donor age was a risk factor for acute GVHD after PTCy-haplo and ATG-haplo. Therefore, we recommend young donors over older donors not only for ATG-haplo PBSCT but also for PTCy-haplo PBSCT.

Different cut-off values for the number of CD34⁺ cells and the limited number of patients in the cohort made it difficult to determine the effect of CD34⁺ cell dose on transplant outcomes after TCR-haplo PBSCT. Consistent with previous studies, a low CD34 cell dose resulted in significantly worse OS and RFS after PTCy-haplo^40–42 but not after ATG-haplo. Concerns about the risk of relapse and worse neutrophil engraftment after PTCy-haplo compared with ATG-haplo may have influenced the results.^8,19,40 We also demonstrated an increased risk of grade III–IV acute GVHD and chronic GVHD in the high CD34⁺ cell dose group only after ATG-haplo. Because our previous studies suggested that ATG-haplo is more disadvantageous than PTCy-haplo in terms of suppressing severe GVHD,^22,43,44 the benefit of an increased cell dose may only be confirmed after PTCy-haplo. Infusion of sufficient CD34⁺ cells (> 4 ×10^6/kg) after PTCy-haplo and not too many CD34⁺ cells (< 7 ×10^6/kg) after ATG-haplo was recommended in this study.

The effect of CMV serostatus after TCR haplo PBSCT has not yet been fully elucidated. For CMV-positive recipients, some reports suggested that CMV-negative donors increased the risk of CMV reactivation and worsened OS compared to CMV-positive donors.⁴⁵ Therefore, the 2017 European Conference on Infections in Leukemia recommended a moderate level of CMV-positive donors for CMV-positive recipients after unrelated donor transplantation with MAC.⁴⁶ In fact, CMV-positive donors showed favorable GRFS after ATG-haplo in our study. In contrast, CMV-positive donors did not affect OS, RFS, or GRFS after PTCy-haplo PBSCT, which was consistent with that observed in previous studies.^47,48 This may be due to the fact that CMV-negative donors were associated with an increased risk of NRM, but significantly reduced the risk of relapse after PTCy-haplo PBSCT in this study. For CMV-negative recipients, donor CMV positivity is a known risk factor for CMV reactivation and mortality.^49,50 This study confirmed that having a CMV-positive donor for a CMV-negative recipient after ATG-haplo is associated with worse GRFS. In contrast, CMV positivity did not affect the outcomes of CMV-negative recipients after PTCy-haplo. Different immunological activities of PTCy and low-dose ATG against CMV reactivation may have affected these results.

Our data also highlighted the impact of donor-recipient kinship on transplant outcomes. We applied IPTW analysis to reduce the effects of various confounding factors and avoid overcorrection in the multivariate analysis. We found that offsprings showed better RFS and GRFS than their siblings after ATG-haplo PBSCT in recipients over 40 years of age. As offspring are younger than siblings in most cases, this result may reflect the effect of donor age on OS after ATG-haplo PBSCT. In recipients under 40 years of age, there was no significant difference between parent and sibling donors, which contrasts with previous reports indicating that parent donors were associated with inferior outcomes compared to sibling donors after PTCy-haplo.^34,37. This discrepancy may stem from previous reports that examined the impact of donor-recipient kinship in PTCy-haplo HSCT using bone marrow as the donor source (62% in Mariotti J et al. and 80% in DeZern AE et al.), where CD34⁺ cell dose was not included as a covariate in the multivariate analysis. Matching for NIMA correlates with a reduced incidence of GVHD after non-TCR-haplo HSCT.^51–53 However, it has not been clarified whether this immunological tolerance is associated with better outcomes in TCR-haplo PBSCT using PTCy or low-dose ATG. In this study, we observed no significant differences between maternal and paternal donors after PTCy-haplo and ATG-haplo, although our study, with a small number of parent donors, may not have sufficient power to demonstrate a statistical difference. Further analysis in this transplant setting, including a comparison between NIMA mismatch siblings and non-inherited paternal antigen mismatch siblings, is warranted.

Finally, we demonstrated comparable outcomes between FD and NFD donors using PS matching. Elmariah et al. first demonstrated the acceptable safety outcomes after PTCy-haplo from NFD using BM with RIC regimens.⁵⁴ Another study showed comparable results between FD and NFD donors in haplo-HSCT using a low-dose ATLG/G-CSF-mobilized PBSCs.⁵⁵ A recent largest study from Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation also showed similar outcomes following FD and NFD haplo-HSCT using ex-vivo T-cell depletion, ATG, PTCy, or the combination of ATG/PTCy for patients with AML or ALL in CR (n = 123).⁵⁶ Our results from JDCHCT are consistent with these previous reports and extend previous findings in that our cohort includes different recipient entities including B-cell lymphoma or high-risk diseases, although larger studies are warranted.

In conclusion, using the largest dataset from the Japanese population, we comprehensively identified the donor characteristics that affected transplant outcomes after TCR-haplo PBSCT using PTCy or low-dose ATG. Although detailed HLA typing, killer cell immunoglobulin-like receptor typing³³, and DSA^57,58 should be considered, our data suggest the following; after PTCy-haplo PBSCT: 1) sufficient CD34⁺ cell numbers (> 4 ×10^6/kg), 2) younger donors over older donors; after ATG-haplo PBSCT: 1) younger donors over older donors, 2) less HLA mismatch donors, 3) not too many CD34⁺ cell numbers (< 7 ×10^6/kg), 4) offspring donors preferred over sibling donor, 5) CMV-negative donors for CMV-negative recipients, and 6) CMV-positive donors for CMV-positive recipients. This study provides comprehensive donor selection strategies according to GVHD prophylaxis using TCR-haplo PBSCT.

Acknowledgments

We thank all the physicians and data managers at the centers who contributed to the collection of data on transplantation for the Japanese Society for Transplantation and Cellular Therapy (JSTCT) and the Transplant Registry Unified Management Program (TRUMP) 2. We also thank the members of the Data Management Committees of the JSTCT and TRUMP for their assistance.

Authors’ Contribution

F.W. and J.K. designed the study, reviewed and analyzed data, and wrote the first draft of the manuscript. M.I., M.H., K.K., and H.N. interpreted data and revised the manuscript; and K.I., N.D., H.N., Y.H., T.F., T.E., N.H., Y.M., K.N., S.O., J.I., T.A., T.I., and Y.A. contributed to data collection. All authors approved the final version.

Competing interests

The authors declare no competing financial interests.

Data Availability

The data that support the findings of this study are available from the corresponding author, JK, upon reasonable request.

Funding

This work was supported in part by the Takeda Science Foundation (JK) and JSPS KAKENHI Grant number 24K11515 (JK).

Ethics Approval

This study was approved by the institutional review board of each center.

Patient consent

Informed consent was obtained from all patients.

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Editorial decision: revise
21 Oct, 2024
Review #2 received at journal
18 Oct, 2024
Review #1 received at journal
25 Sep, 2024
Reviewer #2 agreed at journal
29 Aug, 2024
Reviewer #1 agreed at journal
28 Aug, 2024
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Donor selection in T-cell-replete haploidentical-related donor peripheral blood stem cell transplantation

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Abstract

Figures

Introduction

Participants and Methods

Study patients

Endpoints and statistical analysis

Inverse probability treatment weighting and propensity score matching

Results

Transplant characteristics

OS, RFS, and GRFS

GVHD

Relapse and NRM

Impact of kinship

Offspring vs siblings

Parent vs siblings

Maternal or Paternal

First-degree vs Non-first-degree

Discussions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1