Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative option for children with high-risk acute lymphoblastic leukemia (ALL). This retrospective single-center study analyzed 236 pediatric ALL patients in complete remission who underwent allogeneic HSCT using ex-vivo T cell depletion between 2012 and 2021. The majority received haploidentical grafts (n = 202), while the remainder received matched unrelated donor (MUD) grafts (n = 34). At four years, event-free survival (EFS) and overall survival (OS) were 57% and 67%, respectively. Total body irradiation (TBI)-based conditioning was associated with significantly lower relapse rates and superior EFS compared to chemotherapy-based regimens. Non-relapse mortality (NRM) was low (9%), with no significant difference between donor types. Pre-transplant minimal residual disease (MRD) positivity and transplantation beyond first complete remission were independently associated with higher relapse and inferior survival. Chronic GVHD incidence was lower in patients receiving abatacept and tocilizumab instead of ATG. These findings confirm the safety and efficacy of ex-vivo T cell-depleted HSCT in pediatric ALL, with outcomes comparable between haploidentical and MUD donors. TBI-based conditioning and MRD negativity remain key prognostic factors for improved outcome.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00277-026-06865-w.
Keywords: Acute lymphoblastic leukemia, Allogeneic HSCT, Pediatric, T cell-depleted, HSCT, Long-term follow-up
Introduction
Hematopoietic stem cell transplantation (HSCT) is the standard approach to consolidate remission in children with high-risk acute lymphoblastic leukemia (ALL), either during frontline therapy or after relapse [1, 2]. Historically, the availability of the HLA-matched donor was a critical factor limiting the chance of getting a timely HSCT and, consequently, achieving long-term survival for a patient [3].
More recently, the use of haploidentical family donors revolutionized the field, providing almost universal access to HSCT on time [4]. The technology of haploidentical HSCT evolved and currently includes therapeutic approaches based on either anti-thymocyte globulin (ATG) or high-dose post-transplant cyclophosphamide or various methods of ex-vivo T cell depletion [5, 6].
Depletion of αβ T cells was developed as a platform to mechanically remove effectors of graft-versus-host disease (GVHD) while keeping NK cells and γδ T cells within the graft to capitalize on their anti-leukemia and anti-infection capacity. This method was used by many groups around the globe and was reported to hold significant promise as a safe and effective approach to haploidentical HSCT in children [7–9].
In our center the HSCT program in 2012 adopted the platform of T cell depletion. It was used as a GVHD prophylaxis across all patients with primary HSCT indications, including ALL [10, 11]. Initially, matched unrelated donors (MUD) and haploidentical donors were used equally, but since 2015 priority have been given to haploidentical donors based on the interim analysis, showing slightly higher antileukemic potential with no increase of risk of severe infections or graft failure. Despite several published reports, αβ T-cell depletion is not studied in full detail in large cohort of children with ALL. In the current study, we report long-term outcomes of HSCT and evaluate the impact of factors, such as conditioning regimen, disease status at HSCT, and donor and patient characteristics on survival, relapse incidence, and non-relapse mortality (NRM).
Patients and methods
The aim of the study was to present general outcomes of ab-T-cell depleted HSCT as a platform in the setting of both haploidentical and unrelated HSCT and to evaluate risk factors associated with key clinical outcomes.
A cohort of 236 children (aged < 21 years) with acute lymphoblastic leukemia (PB-ALL, n = 153 and T-ALL, n = 83) in morphological complete remission (CR), who received a first allograft with TCR αβ-T-cell and CD19 depletion between May 2012 and March 2021 at the BMT department of the Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology in Moscow, Russia were enrolled in this retrospective clinical trial, approved by the local Ethical Committee. Written informed consent was obtained from either patients or their legal guardians. In this retrospective single-center study we used the prospectively populated center BMT database.
Two hundred and two patients received haploidentical grafts, and 34 received a graft from MUD. Mothers represented haploidentical donors in 105 and fathers in 97. Initially haploidentical transplantation was performed in patients with unfavorable MUD search results within 3 months. Since January 2015, based on the interim analysis, haploidentical donors were prioritized over MUDs. Median time from leukemia diagnosis (or relapse) to transplantation was 170 days for MUD and 140 days for haplo. Disease status at transplant was a CR1 in 81 pts, CR#2 in 124 pts and CR ≥ 2 in 31 pts. Transplantation in CR1 was performed according to the risk stratification in the contemporary institutional ALL protocol (ALL-MB group protocols, versions 2002, 2008 and 2015) [12]. Multiparameter flow cytometry-based minimal residual disease (MFC-MRD) measurement in bone marrow aspirate was performed within two weeks before conditioning start in 198 patients (84% of the overall cohort). MFC MRD positivity was defined as leukemic population > 0.001% [13]. One hundred forty-three patients were MFC-MRD-negative before HSCT, and 55 were MFC-MRD-positive. Sixty-five patients (39%) with BCP-ALL received Blinatumomab before HSCT.
Baseline characteristics of the group and comparison between the haploidentical and MUD groups are summarized in Table 1.
Table 1.
Demographics and clinical characteristics of patients
| Variable | All n = 236 |
Haplo n = 202 |
MUD n = 34 |
p |
|---|---|---|---|---|
| Patient age, years, median (range) | 8,7(0.5–20) | 8,8(0.5–20.1) | 7,9(0.9–17.5) | |
|
Patient gender (sex): male female |
154 (65%) 82 (35%) |
134 (66%) 68 (34%) |
20 (59%) 14 (41%) |
0.39 |
| CMV IgG+, n (%) | 176 (75%) | 152 (75%) | 24 (71%) | 0.56 |
| CMV IgG-, n (%) | 60 (25%) | 50 (25%) | 10 (29%) | |
| Immunophenotype | ||||
| T- cell ALL, n (%) | 83 (35%) | 68 (34%) | 15 (44%) | 0.23 |
| B-cell precursor ALL, n (%) | 153 (65%) | 134 (66%) | 19 (56%) | |
| Targeted therapy before HSCT | ||||
| Blinatumomab | 65 (28%) | 62 (31%) | 3 (9%) | 0.012 |
| Remission status | ||||
| ALL, CR 1, n (%) | 81 (34%) | 69 (34%) | 12 (35%) | 0.96 |
| ALL, CR 2, n (%) | 124 (53%) | 106 (52%) | 18 (53%) | |
| ALL,> CR2, n (%) | 31(13%) | 27 (14%) | 4 (12%) | |
| MRD flow cytometry pre-HSCT | ||||
| MRD negative, n (%) | 143 (61%) | 131(65%) | 12 (35%) | < 0.0001 |
| MRD positive, n (%) | 55 (23%) | 52 (26%) | 3 (9%) | |
| MRD unknown, n (%) | 38 (16%) | 19 (9%) | 19 (56%) | |
| Conditioning regimen | ||||
| TBI, n (%) | 143 (61%) | 135 (67%) | 8 (24%) | 0.966 |
| Treosulfan -based, n (%) | 93 (39%) | 67 (33%) | 26 (76%) | |
| Serotherapy | ||||
| ATG, n (%) | 73 (31%) | 50 (25%) | 23 (68%) | < 0.0001 |
| Non-ATG, n (%) | 163 (69%) | 152 (75%) | 11(32%) | |
| Donor | ||||
| Age, years, median (range) | 34,5 (2–55) | 34,5 (2–55) | 35 (19–47) | |
| Gender, m:f | 121:115 | 97:105 | 24:10 | 0.015 |
| CMV IgG+, n (%) | 213 (90%) | 183 (91%) | 30 (88%) | 0.668 |
| Graft composition | ||||
| CD34*106/kg | 9.46 (4.1–15.6) | 9.46 (4.1–15.6) | 9.44 (4.6–14.8) | |
| αβ T cells*103/kg | 26 (0.1–361) | 26 (0.1–361) | 29 (2–200) | |
| Follow-up, years, median (range) | 4 (1–10) | 4 (1–9) | 3.9 (1.8–10) | |
Abbrevations: ALL, acute lymphoblastic leukemia; CR1, first complete remission, CR2, second complete remission; HSCT, hematopoietic stem cell transplantation; Haplo, haploidentical donor; MUD, HLA-identical unrelated donor; MRD, minimal residual disease; TBI, total body irradiation
Ninety-three pts (39,4%) received treosulfan-based myeloablative preparative regimen, while a total body irradiation (TBI)-based regimen was used in 143 pts (60,6%). TBI was administered via Helical TomoTherapy or Linear accelerator at a total dose of 12 Gy, as reported [14–16]. Treosulfan was used in combination with either melphalan or thiotepa or etoposide, while TBI was used in combination with either thiotepa or etoposide. Seventy-three patients (31%) received serotherapy, either horse ATG (ATGAM, Pfizer) at 25 mg/kg/day, day − 8, −9 or rabbit ATG (Thymoglobuline, Genzyme) at 2.5 kg/day, day d −5, −4. In a cohort of 163 patients ATG was replaced by abatacept and tocilizumab according to the schedule used in the prospective trial [10].
A full description of the conditioning and GVHD prophylaxis regimens is provided in the supplementary Tables 1 and 2.
Hematopoietic stem cell grafts were derived from a G-CSF-mobilized peripheral blood stem cells, a CXCR4 antagonist (Plerixafor, Mozobil) was used for boosting mobilization of HSC progenitor cells in 70 haploidentical donors (34,6%). αβ-T-cell and CD19 depletion was performed with either a CliniMACS Plus instrument or CliniMACS Prodigy (Miltenyi Biotec, Bergish Gladbach, Germany) according to the manufacturer’s recommendations.
The median log depletion was 4.2 (3.0–5.3.0.3) for αβ-T-cells and 3.2 (2.0–3.9.0.9) for CD19 + cells.
The comparative characteristics of the unrelated and haploidentical donors and grafts are presented in supplementary Table 3.
Supportive care, including GvHD prophylaxis and treatment, was performed according to center-specific and standard guidelines [10].
Engraftment of neutrophils was registered on day 1 of three consecutive days of ANC > 0.5*109/l, and engraftment of platelets was registered on day 1 of three consecutive days of platelet count > 20.0*109/l without prior transfusion.
Lymphohematopoietic chimerism in unfractionated bone marrow (BM), CD34 and CD3 fractions was analyzed monthly until day + 180 using the in-house RT-PCR system for the detection of STR markers.
Statistical analysis
Patient, disease, and transplantation characteristics were summarized using descriptive statistics. Categorical variables are reported as absolute value and percentage, whereas quantitative variables are described as median value and range.
Overall survival (OS) was defined as the probability of survival, regardless of disease status, from the time of HSCT to time of death or of last follow-up (surviving patients were censored at last follow-up, whereas only death was considered an event). For EFS death from any cause and relapse were considered events of interest. NRM was defined as the probability of death from any cause other than malignancy recurrence.
GVHD/relapse-free survival was defined as the probability of survival without occurrence of grade 3 to 4 acute GVHD or chronic GVHD requiring treatment or relapse, whichever occurred first, from the time of HSCT to death or last follow-up.
Acute and chronic GVHD, NRM, and relapse were calculated as cumulative incidence curves in order to adjust the estimates for competing risks. All results were expressed as probability or cumulative incidence (%) and 95% confidence interval (95% CI).
In whole group we performed univariate analysis with a number of factors, reported to correlate with the outcome of HSCT in ALL, including type of leukemia (T-ALL vs. BCP-ALL), CR#, MRD status before HSCT, donor type, patients age and gender, and conditioning.
EFS, OS and GRFS were calculated according to Kaplan-Meyer and compared with log-rank test. XLSTAT, Addinsoft, 2023 software was used for the statistical analysis.
With the aim of better defining the role of alpha-beta T cell depletion we performed multivariable analyses, Cox regression explored the impact of risk factors and conditioning type on OS, EFS, TRM and CIR. Data cut-off on 01.01.2022 with a median follow-up of 4 (0.7–9.4) years in the survivors.
Results
Engraftment, acute and chronic GVHD
Four patients (all after haploidentical HSCT) died before engraftment due to bacterial infections. Primary engraftment was achieved in 227 (98%) patients, surviving till day + 30, with median time to engraftment of 13 days for neutrophils (range, 4–37) and 14 days for platelets (range, 5–84). The CI of neutrophils and platelets was 98% (95%CI: 96–99) and 97% (95%CI: 95–99), respectively.
No difference in the cumulative incidence of neutrophils and platelets engraftment was detected between the haploidentical and unrelated donor groups (p = 0,077 and p = 0,258), the absence of serotherapy increase the CI of neutrophils engraftment (p = 0,006). All engrafted patients had verified morphologic remission and achieved sustained complete donor chimerism by day + 30. Five patients failed to engraft and were rescued with a second HSCT from alternative donors. The median follow-up of surviving patients is 4 (0.7–9.4) years.
The cumulative incidence (CI) of aGVHD grade II-IV was 15% (95% CI, 11–21) (Fig. 1A)., grade III-IV was 6% (95% CI, 3–11). Five patients with aGVHD IV died due to viral and bacterial infection while receiving immunosuppressive therapy. No correlation between donor type, graft composition, serotherapy and aGVHD was noted. (Supplementary Table 4.).
Fig. 1.
Cumulative incidence of acute and chronic GVHD, NRM and relapse (A) Cumulative incidence of grade 2 to 4 acute GVHD in the whole cohort of patients (B) Cumulative incidence of chronic GVHD (all grades). (C) NRM of the whole cohort (D) Cumulative incidence of relapse (CIR) of the whole cohort
Сhronic GVHD developed in 36 pts at a median of 162 days (Fig. 1B.) and was severe in 10 pts. The CI of cGVHD at 2 years was 15% (95%CI: 11–21), 24% (95%CI: 16–36) with serotherapy and 11% (95%CI: 7–17) in patients in whom abatacept and tocilizumab were substituted for ATG, p = 0,010. When comparing СGVHD in groups with Thymoglobulin, ATGAM and without serotherapy the CI of CGVHD was 34% (95%CI: 21–58), 18% (95%CI: 11–33) and 11% (95%CI: 7–17), respectively, p = 0,009. There was no significant difference in the incidence of any cGVHD between the donor type (Supplementary Table 4.) (Fig. 2).
Fig. 2.
Long-term outcomes in whole cohort (A) Overall survival (B) Event-free survival (C) Graft-versus-host disease-free/relapse-free survival (GFRS)
We also compared the cumulative incidence of acute and chronic GvHD between the group of patients who received rabbit ATG and the group who received abatacept, excluding 26 patients who received horse ATG, considering the absence of thymoglobulin, there was no significant difference between these two groups (Supplementary Table 4).. The univariate evaluation of the Impact of Serotherapy on CI of engraftment, aGVHD2-4, aGVHD3-4 and cGVHD, OS, EFS, TRM and Relapse is presented in the supplementary Table 5
Non-relapse mortality
Twenty-two patients, 18 after haplo-HSCT and 4 after MUD-HSCT, died due to causes unrelated to ALL at median of 129 (4–708) days after transplantation (Fig. 1C.). Day + 100 mortality was 2% (95%CI: 1–5). The cumulative incidence of NRM among all patients was 9% (95%CI: 6–14), 9% (95%CI: 6–14) for haploidentical and 12% (95%CI:5–29) for MUD, p = 0,644. The factors, significantly associated with non-relapse mortality in the univariate analysis, were serotherapy during conditioning and MFC-MRD status before HSCT in whole group and also in haplo group as summarized in Table 2. and Supplementary Figs. 1 and 2.
Table 2.
Univariate evaluation of the impact of risk factors and conditioning regimen on NRM and relapse in whole group
| Total | n | Eval. | Death | Relapse | Rejection | CI TRM (95% CI) | p value | CI relapse (95% CI) | p value | CI rejection (95% CI) | p value |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 236 | 137 | 22 | 72 | 5 | 0.09(0.06-0.06,14) | 0.31(0.26–0.38) | 0.02(0,01-0.05.05) | ||||
| Sex | |||||||||||
| male | 154 | 88 | 1 | 52 | 5 | 0.06(0.03–0.11) | p = 0.014 | 0.35(0,28-0.43.43) | p = 0.142 | 0.03(0.01–0.8) | p = 0.100 |
| female | 82 | 49 | 13 | 20 | 0 | 0.16(0.09–0.23) | 0.25(0.17–0.37) | ||||
| Immunophenotype | |||||||||||
| B-cell precursor | 153 | 86 | 16 | 49 | 2 | 0,10(0.07–0.17) | p = 0.427 | 0,33(0,26 − 0,42) | p = 0,601 | 0.01(0,00–0.05.05) | p = 0.240 |
| T-cell ALL | 83 | 51 | 6 | 23 | 3 | 0,07(0.03–0.16) | 0,28(0,20 − 0,4) | 0.03(0.01–0.11) | |||
| MRD - (flow cytometry) pre-HSCT | |||||||||||
| MRD positive | 55 | 26 | 1 | 28 | 0 | 0.02(0.00–0.79.00.79) | p = 0.024 | 0,51(0,39 − 0,66) | p = 0,000 | p = 0.461 | |
| MRD negative | 143 | 94 | 14 | 31 | 4 | 0.10(0.06–0.16) | 0,23(0,17 − 0,31) | 0.02(0.01–0.07) | |||
| MRD unknown | 38 | 17 | 7 | 13 | 1 | 0.18(0.09–0.36) | 0,34(0,22 − 0,52) | 0.02(0.00–0.19.00.19) | |||
| Remission status | |||||||||||
| CR1 | 81 | 54 | 8 | 15 | 4 | 0.10(0.05–0.19) | p = 0.955 | 0.19(0.12–0.30) | p = 0.015 | p = 0.092 | |
| CR2 | 124 | 68 | 11 | 44 | 1 | 0,09(0.05–0.16) | 0.36(0.28–0.45) | 0.04(0.02–0.13) | |||
| > CR2 | 31 | 15 | 3 | 13 | 0 | 0,09(0.03–0.28) | 0.43(0.29–0.65) | 0.01(0.00–0.06.00.06) | |||
| Donor | |||||||||||
| Haploidentical | 202 | 119 | 18 | 60 | 5 | 0.09(0.06–0.14) | p = 0.644 | 0,30(0,25 − 0,38) | p = 0.640 | 0.03(0.01–0.06) | p = 0.355 |
| MUD | 34 | 18 | 4 | 12 | 0 | 0.12(0.05–0.29) | 0,36(0,23 − 0,57) | ||||
| Donor sex | |||||||||||
| male | 121 | 72 | 13 | 34 | 2 | 0.11(0.06–0.18) | p = 0.475 | 0,29(0,22 − 0,39) | p = 0,376 | 0.02(0.00–0.06.00.06) | p = 0.604 |
| female | 155 | 65 | 9 | 38 | 3 | 0.08(0.04–0.15) | 0,34(0,26 − 0,44) | 0.03(0.01–0.08) | |||
| Condition regimen | |||||||||||
| TBI | 143 | 93 | 12 | 36 | 2 | 0.08(0.05–0.15) | p = 0.562 | 0.25(0.19–0.34) | p = 0,062 | 0.01(0.00–0.05.00.05) | p = 0.343 |
| Treo | 93 | 44 | 10 | 36 | 3 | 0.11(0.06–0.19) | 0.39(0.31–0.51) | 0.03(0.01–0.09) | |||
| Serotherapy | 23 | 1 | |||||||||
| ATG | 74 | 39 | 11 | 49 | 4 | 0.15(0.09–0.25) | p = 0.046 | 0.31(0.23–0.44) | p = 0.979 | 0,01(0.00–0,10) | p = 0.594 |
| Non-ATG | 162 | 99 | 11 | 12 | 1 | 0.07(0.04–0.12 | 0.31(0.25–0.40) | 0.02(0.01–0.06) | |||
| Rabbit ATG | 48 | 28 | 7 | 11 | 0 | 0.14(0.07–0.28) | p = 0.15 | 0.25(0.15–0.4) | p = 0.38 | 0.02(0.003–0.15) | p = 0.72 |
| ATGAM | 26 | 11 | 4 | 49 | 4 | 0.15(0.06–0.37) | 0.42(0.27–0.66) | 0.07(0.04–0.12) | |||
| Non-ATG | 162 | 98 | 11 | 0.07(0.04–0.12) | 0.07(0.04–0.12) | ||||||
| Graft composition CD34 | |||||||||||
| < m | 118 | 65 | 11 | 41 | 1 | 0.09(0.05–0.16) | p = 0.982 | 0.35(0.28–0.46) | p = 0.196 | 0.01(0.00–0.06.00.06) | p = 0.179 |
| > m | 118 | 72 | 11 | 31 | 4 | 0.09(0.05–0.17) | 0.27(0.20–0.36) | 0.03(0.01–0.08) | |||
| TCR a/b | |||||||||||
| < m | 119 | 70 | 10 | 38 | 1 | 0.08(0.04–0.15) | p = 0.652 | 0.32(0.25–0.42) | p = 0.605 | 0.01(0.00–0.06.00.06) | p = 0.169 |
| > m | 117 | 67 | 12 | 34 | 4 | 0.10(0.06–0.18) | 0.30(0.23–0.40) | 0.04(0.01–0.09) |
Abbreviations: ALL, acute lymphoblastic leukemia; CR1, first complete remission, CR2, second complete remission; HSCT, hematopoietic stem cell transplantation; MUD, HLA-identical unrelated donor; MRD, minimal residual disease; TBI, total body irradiation; Treo, treosulfan; NRM, non-relapse mortality; CI, cumulative incidence; ATG- antithymocyte globulin
The direct causes of non-relapse death were bacterial infections in 6, viral infections in 3, including 2 pts with COVID 19. Twelve of those 22 patients had aGVHD, were on systemic corticosteroid therapy at time of development fatal complications and died after combined (bacterial, viral and mycosis) complication. One patient died after unknown severe lung injury.
In multivariate analysis donor type, preparative regimen, serotherapy, CMV reactivation, number of relapses, previous MFC-MRD status were neither significantly associated with NRM (Table 2.)
Leukemia relapse
Seventy-two children relapsed at a median time of 160 days (range, 39–1145 days) after the allograft. Among the relapsed patients, 35 received further therapy and 29 underwent second HSCT. Twenty-two of the relapsed patients are alive and remain in CR with median f-up of 245 days after the second transplantation. The CIR at 4 years was 31% (95%CI: 26–38) in the entire cohort. A pre-HSCT detectable MFC-MRD or unknown MFC-MRD status and CR > 1 was associated with increased risk for relapse in the univariate analysis with p = 0.000 and 0.015 respectively (Table 2.).
Patients with BCP-ALL who received TBI had a significantly low relapse rate with p = 0.026 at that time TBI regimen was not associated with decreased relapse rate in T-ALL, p = 0.970.
Lower risk of relapse was observed among patients with cGVHD, 6% versus 31%, p = 0.04. Previous blinatumomab therapy in BCP-ALL was associated with high relapse rate, 43% vs. 27% with p = 0.039.
Among group with haploidentical donors CIR was 25% (95%CI: 18–36) in patients with high CD 34 cells level in the graft and 36% (95%CI: 28–47) with low, p = 0.075. In patients who have received who have received graft mobilized with plerixafor in addition to G-CSF CIR was 38% (95%CI: 28–51) in comparison to 27% (95%CI: 20–36) in non-stimulated graft with p = 0.085 (Supplementary Fig. 3.).
Patients age, donor type, preparative regimen, serotherapy, CMV reactivation, KIR mismatch (in haplo group) and sybtype of ALL were not significantly associated with CIR in a univariate analysis (Table 3).
Table 3.
Univariate evaluation of the impact of risk factors and conditioning regimen on OS, EFS
| Overall Survival | Event-free Survival | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| n | Eval. | Deaths | year OS (95% CI) | p value | n | Eval. | Events | year EFS (95% CI) | p value | |
| Total | 236 | 162 | 74 | 0.67(0.60-0.60,73) | 236 | 137 | 99 | 0.57(0.51–0.64) | ||
| Sex | ||||||||||
| Male | 154 | 106 | 48 | 0.67(0.59–0.75) | p = 0.968 | 154 | 88 | 66 | 0.56(0.48–0.64) | p= 0.604 |
| female | 82 | 56 | 26 | 0.67(0.56–0.77) | 482 | 49 | 33 | 0.59(0.49–0.70) | ||
| Immunophenotype | ||||||||||
| B-cell precursor | 153 | 105 | 48 | 0.66(0.58–0.74) | p = 0.863 | 153 | 86 | 67 | 0,55(0.46–0.63) | p = 0.631 |
| T-cell | 83 | 57 | 26 | 0.68(0.57–0.78) | 83 | 51 | 32 | 0.61(0.50–0.72) | ||
| MRD - (flow cytometry) pre-HSCT | ||||||||||
| MRD positive | 55 | 32 | 23 | 0.58(0.45–0.71) | p = 0.002 | 55 | 26 | 29 | 0.47(0.34–0.61) | p = 0.015 |
| MRD negative | 143 | 111 | 32 | 0.75(0.67–0.80) | 143 | 94 | 49 | 0.64 (0.56–0.72) | ||
| MRD unknown | 38 | 19 | 19 | 0.49(0.33–0.65) | 38 | 17 | 21 | 0.45(0.29–0.60) | ||
| Remission status | ||||||||||
| CR1 | 81 | 64 | 17 | 0.78(0.68–0.87) | p = 0.091 | 81 | 54 | 27 | 0.66(0.55–0.76) | p = 0.208 |
| CR2 | 124 | 79 | 45 | 0.62(0.54–0.71) | 124 | 68 | 56 | 0.54(0.45–0.63) | ||
| > CR2 | 31 | 19 | 12 | 0.59(0.41–0.77) | 31 | 15 | 16 | 0.47(0.29–0.65) | ||
| Donor | ||||||||||
| Haploidentical | 202 | 142 | 60 | 0.69(0.62–0.75) | p = 0.307 | 202 | 119 | 83 | 0.58(0.5–0.65) | p = 0.782 |
| MUD | 34 | 20 | 14 | 0.58(0.41–0.75) | 34 | 18 | 16 | 0.52(0.35–0.69) | ||
| Donor sex | ||||||||||
| male | 121 | 85 | 36 | 0.68(0.59–0.76) | p = 0.507 | 121 | 72 | 49 | 0.58(0.49–0.67) | p = 0.461 |
| female | 115 | 77 | 38 | 0.66(0.57–0.74) | 115 | 65 | 50 | 0.56(0.47–0.65) | ||
| Condition regimen | ||||||||||
| TBI | 143 | 102 | 41 | 0.69(0.62–0.78) | p = 0.364 | 143 | 93 | 50 | 0.46(0.36–0.56) | p = 0.019 |
| Treo | 93 | 60 | 33 | 0.62(0.52–0.73) | 93 | 44 | 49 | 0.64(0.56–0.72) | ||
| Serotherapy | ||||||||||
| ATG | 74 | 43 | 31 | 0.58(0.46–0.69) | p = 0.025 | 74 | 39 | 35 | 0.53(0.41–0.64) | p = 0.258 |
| Non-ATG | 162 | 119 | 43 | 0.71(0.63–0.78) | 162 | 98 | 64 | 0.59(0.51–0.67) | ||
| Rabbit ATG | 48 | 31 | 17 | 0.65(0.51–0.78) | p = 0.039 | 48 | 28 | 20 | 0.58(0.44–0.72) | p = 0.383 |
| ATGAM | 26 | 12 | 14 | 0.46(0.27–0.65) | 26 | 11 | 15 | 0.42(0.23–0.61) | ||
| Non-ATG | 162 | 119 | 43 | 0.71(0.63–0.78) | 162 | 98 | 64 | 0.59(0.51–0.67) | ||
| Graft composition CD34 | ||||||||||
| < m | 118 | 80 | 38 | 0.66(0.57–0.75) | p = 0.805 | 118 | 65 | 53 | 0,54(0.45–0.63) | p = 0.454 |
| > m | 118 | 82 | 36 | 0.68(0.59–0.77) | 118 | 72 | 46 | 0.60(0.51–0.69) | ||
| TCRa/b | ||||||||||
| < m | 119 | 83 | 36 | 0.69(0.61–0.77) | p = 0.782 | 119 | 70 | 49 | 0.58(0.49–0.67) | p = 0.867 |
| > m | 117 | 79 | 38 | 0.65(0.55–0.74) | 117 | 67 | 50 | 0.56(0.46–0.65) | ||
Abbreviations: ALL acute lymphoblastic leukemia, CR complete remission, HSCT hematopoietic stem cell transplantation, MUD HLA-identical unrelated donor, MRD minimal residual disease, TBI total body irradiation, Treo treosulfan, NRM non-relapse mortality, CI cumulative incidence, ATG antithymocyte globulin
In multivariate analysis serial number of CR (> 1), pre HSCT MFC-MRD positivity significantly impacted on for relapse rate (SHR 3.44 (95%CI1.83-6.45.45); p < 0.001 and 3.86 (95%CI 2.28–6.54); p < 0.001). The CIR was low (SHR 0.41 (0.24–0.72); p = 0.002) for patients transplanted with TBI (Fig. 3., Table 4.).
Fig. 3.
Forrest plot showing subgroup analyses of overall survival, event- free survival, non-relapse mortality and CI of relapse by risk factor and conditioning regimen. ALL, acute lymphoblastic leukaemia; CR, complete remission; MRD, minimal residual disease; TBI, total body irradiation; ATG, ATG- antithymocyte globulin; Mel, melphalan
Table 4.
Multivariable analyses of the impact of risk factors OS, EFS, TRM and relapse in whole group
| Variable | OS | EFS | NRM | CIR | ||||
|---|---|---|---|---|---|---|---|---|
| HR1 (95%CI) | p | HR1 (95%CI) | p | SHR2 (95%CI) | p | SHR2 (95%CI) | p | |
| Remission rate | ||||||||
| CR2-3 vs. CR1 | 2.08 (1.12–3.84) | 0.020 | 1.79 (1.09–2.96) | 0.022 | 0.49 (0.15–1.59) | 0.230 | 3.44 (1.83–6.45) | < 0.001 |
| MRD pre HST vs. MRD - | ||||||||
| MRD + | 2.13 (1.23–3.66) | 0.007 | 2.01 (1.26–3.22) | 0.004 | 0.16 (0.02–1.14) | 0.068 | 3.86 (2.28–6.54) | < 0.001 |
| MRD n/e | 2.17 (1.03–4.56) | 0.040 | 1.83 (0.93–3.59) | 0.080 | 1.51 (0.41–5.54) | 0.530 | 1.83 (0.81–4.14) | 0.150 |
| Conditioning regimen | ||||||||
| Treo/Mel vs. other | 3.92 (1.49–10.3) | 0.006 | 1.89 (0.85–4.24) | 0.120 | 7.72 (0.92–64.9) | 0.060 | 1.42 (0.54–3.76) | 0.480 |
| TBI vs. other | 1.23 (0.61–2.48) | 0.561 | 0.60 (0.36–1.02) | 0.058 | 3.59 (0.86–15.0.86.0) | 0.079 | 0.41 (0.24–0.72) | 0.002 |
| Diagnosis | ||||||||
| T-ALL vs. B-ALL | 1.17 (0.67–2.03) | 0.589 | 1.10 (0.68–1.80) | 0.689 | 0.41 (0.12–1.38) | 0.150 | 1.35 (0.77–2.36) | 0.290 |
| Serotherapy | ||||||||
| ATG + vs. ATG - | 0.64 (0.30–1.38) | 0.257 | 0.58 (0.29–1.14) | 0.111 | 1.36 (0.29–6.36) | 0.700 | 0.41 (0.17–1.01) | 0.053 |
| CMV reactivation | ||||||||
| CMV react vs. non react. | 1.21 (0.74–1.97) | 0.447 | 1.02 (0.68–1.55) | 0.913 | 1.06 (0.38–2.97) | 0.920 | 0.99 (0.62–1.57) | 0.960 |
| Donor type | ||||||||
| MUD vs. Haplo | 0.55 (0.24–1.22) | 0.141 | 0.62 (0.30–1.27) | 0.188 | 0.38 (0.09–1.58) | 0.180 | 0.88 (0.41–1.89) | 0.750 |
| CR, complete remission; MRD, minimal residual disease; n/e, non-evaluated; TBI, total body irradiation; ALL, acute lymphoblastic leukemia; BCP- B-cell precursor, Treo, treosulfan; Mel, melphalan; HR, Hazard Ratio; SHR, Subdistribution Hazard Ratio | ||||||||
Cumulative incidence of relapse and transplant-related mortality outcomes of the whole group are summarized and illustrated in Table 2.
Event-free survival and overall survival
EFS and OS at 4 years were 57% (95% CI: 51–64) and 67% (95% CI: 61–73), respectively, for the entire cohort as shown in Figs. 2A and B. The 4-year probability of EFS and OS for patients given either Haplo-HSCT or MUD-HSCT were 58% and 69%, vs. 52% and 58%, respectively (p - n.s.) (Table 3). The 4-year GRFS in the whole group was 55% (95%CI: 49–62) (Fig. 2C.).
Use of TBI regimen had a significant positive correlation with event-free survival outcomes: EFS for TBI 64% (95%CI: 56–72) and for non-TBI 46% (95%CI: 36–56), p = 0.019, without influence on OS. Serotherapy in preparative regimen significantly associated with worse OS with p = 0.025 without effect on EFS p = 0.258 (Supplementary Fig. 4 AB and CD).
Drug combinations within TBI- and non-TBI regimens might not be equal, but the power of the current analysis is insufficient to prove the difference (Table 3). In the univariate analysis a pre-HSCT MFC-MRD positivity or unknown MFC-MRD status were associated with poorer outcome: OS with p = 0.002 and EFS with p = 0.015; see Table 3 for details.
Other tested factors were not associated with statistically significant difference in either EFS or OS in univariate analysis. These results are shown in Table 3.
In haploidentical group the probability of OS and EFS at four years was 69% (95%CI: 62–75) and 59% (95%CI: 62–75) respectively. The 4-year GRFS was 56% (95%CI: 49–63). In univariate analysis, MFC-MRD negativity before HSCT, TBI-based conditioning regimen, high dose of CD34 in the graft predicted better EFS (p < 0.063, p = 0.046, and p = 0.016, respectively) (Supplementary Fig. 5, panels A, B and C respectively).
In multivariate analysis serial number of CR (> 1), positive pre-HSCT MFC-MRD reached statistical significance for OS (HR 2.08 (95%CI 1.12–3.84); p = 0.02 and 2.13 (1.23–3.66); p = 0.007), for EFS (HR 1.79 (95%1.09–2.96); p = 0.022 and 2.01 (1.26–3.22); p = 0.004), EFS was high (HR, 0.6 (95%CI 0.36–1.02); p = 0.058) for patients transplanted with TBI (Fig. 3., Table 4.).
Discussion
High-risk and relapsed ALL remains one of the predominant indications for HSCT in the children [17]. Despite a long history of research and clinical practice, a number of issues remain unresolved. The use of haploidentical donors revolutionized the field and two platforms of GVHD prevention are widely used: PtCy and ex-vivo T-cell depletion.
Depletion of αβ-T-cells entered the clinical practice just over a decade ago [18]. HLA-mismatch and specific graft composition, enriched in NK cells and γδ-T-cells, was expected to provide additional anti-leukemia activity and improved control of infections, despite the profound depletion of conventional αβ-T-cells [19–22].
Most published reports on αβ T-cell depletion rely on ATG preparations to ensure engraftment and GVHD control in haploidentical HSCT [9, 22].
In view of these, we initiated the retrospective analysis of a large cohort of children with ALL transplanted with αβ-T-cell-depleted grafts and two different GVHD prophylaxis (with and without serotherapy). Haploidentical donors represent over 85% of the cohort, and MUDs constitute the remaining part.
The depletion of TCR-alpha/beta and CD19 lymphocytes from the graft in this cohort of pediatric ALL patients with median follow-up of 4 years ensures high engraftment rate and low incidence of severe GVHD without correlation between donor type and GVHD prophylaxis regimen.
The low incidence of chronic GVHD in the group of patients who did not receive serotherapy requires a more detailed analysis, including the investigation of the potential role of the combination of TCR-alpha/beta depletion and abatacept. However, after excluding patients who received horse ATG (ATGAM) from the analysis, these differences disappear. We hypothesized that the relatively high rate of GVHD in ATGAM group could partly be explained by the known lower activity of horse ATG.
NRM primarily associated with bacterial and viral infections was quite low in the general cohort, but higher in the group of patients who received serotherapy in univariate analysis, however, this significance disappears in the multivariate analysis.
Pre-transplant residual leukemia [24] and the number of previous attempts to cure with conventional chemotherapy were previously reported as important prognostic factors or relapse and overall success of HSCT.
Disease relapse remains the main cause of treatment failure in our trial, particularly in patients with high levels of pre-HSCT MRD and more advanced CR.
Previous blincyto therapy in BCP-ALL associated with high relapse rate in univariate analyses, but not in multivariate setting. It does not seem probable that blinatumomab itself influences negatively the incidence of relapse, but rather blinatumomab was administered to patients with highest relapse risk, i.e., patient’s refractory to intensive chemotherapy)
In the current analysis, detectable pre-HSCT MFC-MRD was shown to be significantly associated with higher relapse incidence and lower EFS and OS, both in the univariate and multivariate analysis in the whole group.
Unfortunately, it is not possible to assess the reliability of the impact of pre-HSCT MFC-MRD in the overall group due to the large number of patients with unknown MRD status prior to HSCT in the group transplanted from an unrelated donor (56%) compared to haploidentical group (9%).
TBI historically was the cornerstone of myeloablation and host immunosuppression before HSCT in ALL patients. In our cohort, TBI was prioritized over chemotherapy-based regimens and depending on technical availability among children > 4 years old. Univariate analysis demonstrated the high safety of TBI in combination with either thiotepa or etoposide, a trend towards lower relapse incidence and clearly superior EFS. Multivariate analysis confirmed an independent significant effect of TBI on the incidence of leukemia relapse and EFS without effect on OS. This finding is consistent with the data obtained in the For Omitting Radiation Under Majority age (FORUM) randomized clinical trial [18].
Our results presented should be viewed with the limitation of the retrospective nature of the study. The cohorts we compared (Haploidentical and match-unrelated donor group) differed significantly in a number of important basic characteristics (MRD status before HSCT and use of serotherapy). Despite this, we believe that it confirms multiple reports suggesting at least equal outcomes of MUD and haploidentical HSCT. This data further justifies the approach to donor choice which does not give priority to MUD and includes the optimal timing of HSCT as the key parameter.
To conclude, we believe that this analysis further confirms the power of the graft manipulation approach, which increases the safety of HLA-mismatched HSCT among children with ALL what was also shown in the latest analysis of Merli and colleagues (Merli et al., Blood 2024) [23].
The ATG-free regimen based on abatacept and tocilizumab is safe and prevents GVHD at least as well as ATG at the TCR alpha-beta depletion platform which also confirms our previous research [25].
Patients with pre-HSCT positive MRD status had a high risk of treatment failure and require additional approaches aimed at reducing relapse development, despite the re-confirmed role of TBI.
In this context, the strategy of TCR alpha-beta depletion confirm the good outcome results in patients received allogenic graft from matched unrelated and haploidentical donors.
A positive MRD status before HSCT requires additional therapeutic methods (targeted, cellular therapy), which are possible with TCR platform-based HSCT and the potential to discontinue serotherapy during conditioning.
Supplementary Information
Below is the link to the electronic supplementary material.
Author contributions
M. M. and L. S. wrote the main manuscript text K. V. - statistical analysisAll authors - drafted the work or revised it critically for important intellectual content; approved the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
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Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.