Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

doi:10.21203/rs.3.rs-3744328/v1

Download PDF

Research Article

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

https://doi.org/10.21203/rs.3.rs-3744328/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 28 Nov, 2023

Read the published version in Blood →

Version 1

posted

You are reading this latest preprint version

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A control (CON) group of 82 patients received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 38.4%, P= 0.030), better 2-year LFS (76.1 vs. 51.6%, P = 0.027), and had a trend towards better 2-year OS (80.5 vs. 60.4%, P= 0.063). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year OS and LFS, despite no significant differences (75.0 vs. 18.6%, P = 0.068; 75.0 vs. 24.1%, P = 0.070, respectively). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 39.0%, P = 0.820). The most common non-hematologic adverse event was gastrointestinal tract. Hepatic dysfunction was more often observed in the Chi group. 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P= 0.021). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT.

Allogeneic stem cell transplantation

Conditioning regimen

T acute lymphoblastic leukemia/lymphoma

histone deacetylase inhibitors.

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) has a poor response to chemotherapy and an extremely bad prognosis due to its tendency to high white blood cells, central nervous system, and extramedullary infiltration[1–5]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment[6, 7]. However, the cumulative incidence of post-transplant relapse in T-ALL/LBL was 30 to 50%, constituting a major cause of patient mortality [8–12]. And the 2-year overall survival (OS) probability after relapse was about 10 to 46%[12–14]. Intensifying conditioning regimens is one of the potential ways to reduce relapse rates. The modified Bu-Cy (mBuCy) conditioning regimen is the predominant myeloablative therapy in China, owing to its low transplant-related mortality and efficient hematopoietic reconstitution[15, 16]. However, when administered to T-ALL/LBL patients, this regimen remains limited by its inability to eliminate minimal residual disease (MRD) and high incidence of relapse following transplantation. Therefore, further refinement and optimization of the T-ALL/LBL conditioning regimen is imperative.

As the first oral subtype-selective histone deacetylase inhibitor (HDACi) approved in China[17], the real-world study has demonstrated that chidamide has a favorable efficacy and an acceptable safety profile for T-lymphocytic malignancies patients[18]. Chidamide could inhibit proliferation and induce apoptosis via cell cycle arrest and the regulation of apoptotic proteins in T-cell malignancies[19, 20]. Of note, chidamide combined with chemotherapy regimens can decrease MRD in T-ALL patients with NOTCH1 mutation[21]. Given its promising antitumor activity and synergistic effects, Ji et al. incorporated chidamide into the lymphoma pretreatment regimen (ChiCGB). The 4-year progression-free survival (PFS) and OS rates for high-risk or relapsed/refractory lymphomas were significantly improved, reaching 80.6% and 86.1%, respectively[22]. To date, the role of chidamide in T-ALL/LBL conditioning regimens in allo-HSCT has not been explored. Here, we retrospectively compared the clinical efficacy and safety between mBuCy combined with chidamide and mBuCy conditioning regimen for T-ALL/LBL patients undergoing allo-HSCT.

Patients

We conducted a retrospective study at the First Affiliated Hospital of Soochow University between December 21, 2017, and February 21, 2022, to evaluate the safety and efficacy of the chidamide-containing conditioning regimen for high-risk T-ALL/LBL. 22 patients received the chidamide combined with modified Bu-Cy regimen (Chi group), and 82 patients received only modified Bu-Cy (CON group) and underwent allo-HSCT during the same period. This study was approved by the ethics committee of the First Affiliated Hospital of Soochow University, and all patients provided written informed consent before treatment in accordance with the Helsinki Declaration.

Conditioning regimens

Patients in the Chi group received chidamide in combination with the mBuCy as a conditioning regimen. If the donors were haploidentical type, chidamide was administered 15mg orally on days − 14, -12, -9, -7, and − 5 before chemotherapy. The patients received Me-CCNU 250 mg/m²/d orally on day − 12, cytarabine 2 g/m² i.v. every 12h on days − 11 to − 10 for a total of 4 doses, busulfan 0.8 mg/kg i.v. every 6h on days − 9 to − 7 (12 doses), and cyclophosphamide 1.8g/m²/d i.v. on days − 5 and − 4. If the donors were HLA-matched siblings or unrelated types, chidamide was administered 15mg orally on days − 11, -9, -7, and − 5 before chemotherapy. The patients received Me-CCNU 250 mg/m²/d orally on day − 11, cytarabine 2 g/m² i.v. every 12h on day − 10, busulfan 0.8 mg/kg i.v. every 6h on days − 9 to − 7 (12 doses), and cyclophosphamide 1.8 g/m²/d i.v. on days − 5 and − 4. Patients in the CON group only received the same mBuCy regimen except for chidamide.

Graft-versus-host disease prophylaxis

The graft-versus-host disease (GVHD) prophylaxis protocol is the same as our center's previously published study[23, 24]. The prophylaxis regimen included cyclosporine A (CsA) with short-course methotrexate (MTX) for related identical donor transplantation, and CsA, short-course MTX, mycophenolate mofetil (MMF), and rabbit anti-thymocyte globulin (Thymoglobulin™) for unrelated and haploidentical transplantation. CsA 3 mg/kg/d was continuously infused for 24h from day − 9, of which the trough concentration was adjusted to 150–200 ng/ml. It was switched to oral administration when the patient’s bowel function normalized again after the transplant. From day − 9, 0.5 g of MMF was administered orally every 12h and was discontinued on day + 28 post-transplant. Short-course MTX was administered on days + 1 (15 mg/m²), + 3, +6, and + 11 (10 mg/m²). Rabbit-ATG (2.5 mg/kg/d, i.v.) was used from day − 5 to − 2.

Definitions and statistical methods

OS was the time from transplantation to death. Leukemia-free survival (LFS) was the time from transplantation to leukemia relapse, death, or last follow-up. Non-relapse-related mortality (NRM) was defined as the time from transplantation to death of any causes other than hematologic disease relapse. Relapse was defined as the reappearance of leukemia cells (≥ 5%) in the peripheral blood or bone marrow of patients in complete remission or the development of extramedullary disease. Refractory was defined as (1) Failure of initial induction therapy after two or more courses of treatment; (2) early recurrence less than 6 months after the first remission; (3) inefficacy to response to induction chemotherapy after recurrence; and (4) multiple relapses. For univariate comparison, the Mann–Whitney U test was used for continuous variables, and the chi-square test or Fisher’s exact test for categorical variables. The Cox proportional hazards model was used for univariate and multivariate analysis. OS and LFS were estimated by the Kaplan–Meier method and compared by using the log-rank test. The CIR was estimated using Gray’s sub-distribution method to account for the presence of competing risk due to non-relapse mortality. P values < 0.05 were considered significant. All analyses in this study were performed using the IBM Statistical Package for Social Sciences version 25 and R version 4.1.2.

Patient enrollment and characteristics

104 patients with T-ALL/LBL were screened and enrolled, and 22 patients received a chidamide-containing conditioning regimen. Patients’ characteristics are shown in Table 1. The median age at transplantation was 28 (range, 19–36) years, and 79 (76.0%) of 104 patients were male. The median time from diagnosis to HSCT was 175 (range, 115–215) days. The pre-transplant characteristics were similar between the two groups.

Table 1

Transplant characteristics
Characteristic	Total	Chi (n = 22)	CON (n = 82)	P value
Gender, n (%)
Male	79 (76.0)	19 (86.4)	60 (73.2)	0.266
Female	25 (24.0)	3 (13.6)	22 (26.8)
Median age, years (range)	28 (19–36)	29 (18–34)	27 (19–36)	0.933
Diagnosis, n (%)
T-ALL	54 (51.9)	11 (50.0)	43 (52.4)	0.973
T-LBL	23 (22.1)	5 (22.7)	18 (22.0)
ETP-ALL	16 (15.4)	4 (18.2)	12 (14.6)
T/M MPAL	11 (10.6)	2 (9.1)	9 (11.0)
Time from diagnosis to HSCT (d), median (range)	175 (115–215)	185 (147–280)	168 (107–214)	0.064
Status of disease before HSCT, n (%)
CR1	81 (77.9)	17 (77.3)	64 (78.0)	0.981
≥CR2	13 (12.5)	3 (13.6)	10 (12.2)
Non-CR	10 (9.6)	2 (9.1)	8 (9.8)
MRD status before HSCT, n (%)
Negative	77 (74.0)	18 (81.8)	59 (72.0)	0.349
Positive	27 (26.0)	4 (18.2)	23 (28.0)
Donor type, n (%)
Haplo	81 (77.9)	17 (77.3)	64 (78.0)	0.694
SIB	10 (9.6)	3 (13.6)	7 (8.5)
URD	13 (12.5)	2 (9.1)	11 (13.4)
Donor-recipient gender match, n (%)
Male-male	63 (60.6)	13 (59.1)	50 (61.0)	0.417
Male-female	19 (18.3)	3 (13.6)	19 (23.2)
Female-male	15 (14.4)	3 (13.6)	9 (11.0)
Female-female	7 (6.7)	3 (13.6)	4 (4.9)
Donor-recipient ABO match, n (%)
Match	36 (34.6)	4 (18.2)	32 (39.0)	0.068
Mismatch	68 (6.5)	18 (81.8)	50 (61.0)
Stem cell source, n (%)
PBSC	78 (75.0)	19 (86.4)	59 (72.0)	0.267
PBSC + BM	26 (25.0)	3 (13.6)	23 (28.0)
Number of cells infused, median (range)
MNC (×10⁸/kg)	9.2 (6.4–11.9)	8.5 (5.6–11.2)	9.2 (6.6–12.0)	0.548
CD34+(×10⁶/kg)	3.7 (2.9–5.2)	3.8 (2.8–5.6)	3.6 (2.9–5.1)	0.937
CD3+(×10⁸/kg)	1.4 (1.1–1.8)	1.6 (1.3–1.8)	1.3 (1.1–1.8)	0.083
Poor risk factors, n (%)
Age > 35 years at diagnosis	29 (27.9)	5 (22.7)	24 (29.3)	0.544
WBC > 100 ×10⁹/L at diagnosis	21 (20.2)	7 (31.8)	14 (17.1)	0.126
Extramedullary disease at diagnosis	49 (47.1)	12 (54.5)	37 (45.1)	0.432
Complex karyotype	19 (18.3)	5 (22.7)	14 (17.1)	0.542
Relapsed or refractory	32 (30.8)	8 (36.4)	24 (29.3)	0.522
T-ALL T acute lymphoblastic leukemia, T-LBL T acute lymphoblastic lymphoma, ETP-ALL early T-cell precursor acute lymphoblastic leukemia, T/M MPAL T/myeloid mixed phenotype acute leukemia, HSCT hematopoietic stem cell transplantation, CR complete remission, MRD minimal residual disease, Haplo Haploidentical donors, SIB HLA-matched sibling donors, URD HLA-matched unrelated donors, PBSC peripheral blood stem cells, BM bone marrow, WBC white blood cell.

Engraftment and GVHD

All patients achieved hematopoietic reconstitution. The neutrophil engraftment in Chi and CON groups occurred at 11 (range, 11–13) days and 11 (range, 11–12) days (P = 0.386), respectively. Platelet engraftment time was 13 (range 11–15) days in the Chi group and 14 (range 12–14) days in the CON group (P = 0.319), respectively. The incidences of day 100 grade II–IV (36.4 vs. 39.0%; P = 0.820) and III–IV (13.6 vs. 18.3%; P = 0.845) aGVHD were not significantly different between Chi and CON groups, respectively. There was no difference in the incidence of 2-year cGVHD between the Chi group and CON group (36.4 vs. 39.0%, P = 0.820) (Table 2).

Table 2

Incidence of engraftment, GVHD, and adverse events after allo-HSCT
Engraftment, GVHD, and adverse events, n (%)	Chi group	CON group	P value
Engraftment
Time of neutrophil reconstruction(d), median(range)	11 (11–13)	11 (11–12)	0.386
Time of platelet reconstruction(d), median(range)	13 (11–15)	14 (12–14)	0.319
GVHD
aGVHD	11 (50.0)	47 (57.3)	0.539
grade II-IV aGVHD	8 (36.4)	32 (39.0)	0.820
grade III-IV aGVHD	3 (13.6)	15 (18.3)	0.845
cGVHD	8 (36.4)	32 (39.0)	0.820
Infection
EBV reactivation	8 (36.4)	17 (20.7)	0.128
CMV reactivation	9 (40.9)	36 (43.9)	0.801
Pneumonia	12 (54.6)	41 (50.0)	0.705
Perianal Infection	2 (9.1)	2 (2.4)	0.414
Hemorrhagic cystitis	8 (36.4)	16 (19.5)	0.096
Urinary tract infection	2 (9.1)	2 (2.4)	0.414
Soft tissue skin infection	0 (0)	2 (2.4)	1.000
Sinusitis	4 (18.2)	4 (4.8)	0.103
Sepsis	3 (13.6)	6 (7.3)	0.611
Gastrointestinal disorder
Nausea	12 (54.5)	52 (74.3)	0.079
Vomiting	8 (36.4)	40 (57.1)	0.089
Diarrhea	13 (59.1)	45 (54.9)	0.724
Bloating	4 (18.2)	9 (11.0)	0.466
Hepatic dysfunction
Increase of γ-glutamyl transferase	20 (90.9)	54 (65.9)	0.021
Increase of lactate dehydrogenase	10 (45.5)	45 (54.9)	0.432
Increase of total serum bilirubin	7 (31.8)	21 (25.6)	0.318
Increase of alanine aminotransferase	8 (36.4)	37 (45.1)	0.462
Increase of aspartate aminotransferase	8 (36.4)	37 (45.1)	0.462
Increase of alkaline phosphatase	6 (27.3)	15 (18.3)	0.527
Renal insufficiency
Increase of creatinine	2 (9.1)	2 (2.4)	0.196
Positive urine protein	8 (36.4)	28 (34.1)	0.762
Positive urine erythrocytes	4 (18.2)	30 (36.4)	0.102
Positive urine leukocytes	4 (18.2)	26 (31.8)	0.214
Others
Mucositis	12 (54.6)	58 (70.7)	0.151
Intracranial hemorrhage	0 (0)	3 (3.7)	1.000
Pancreatitis	0 (0)	4 (4.9)	0.576
Epilepsy	0 (0)	4 (4.9)	0.576
NRM: non-relapse related mortality, aGVHD acute graft-versus-host disease, cGVHD chronic graft-versus-host disease, CMV cytomegalovirus, EBV Epstein-Barr virus.

Safety

Consistent with patients in the CON group, all patients in the Chi group manifested severe myelosuppression. The foremost non-hematologic adverse event (AE) observed was gastrointestinal tract reactions including diarrhea (Chi group, 59.1%; CON group, 54.9%; P = 0.724) and nausea (Chi group, 54.5%; CON group, 74.3%; P = 0.079). Hepatic dysfunction was more often observed in the Chi group. 20 patients evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, respectively; P = 0.021). (Table 2).

Seventeen (77.3%) patients administered the Chi regimen developed treatment-related infections, primarily pneumonia (54.6%). Severe adverse events including sepsis were reported in 3 cases (13.6%) of the Chi group and 6 cases (13.6%) of the mBuCy group (P = 0.611) (Table 2). All three cases in the Chi group were gram-negative infections. No instances of treatment-related death were reported in the Chi group during the treatment period.

Non-relapse related mortality and Overall Survival

The median follow-up time in the Chi group was 733 (range 368–1255) days, while that of the CON group was 693 (range 270–1166) days. There was a trend towards better OS in the Chi group compared to the CON group (80.5 vs. 60.4%, P = 0.063, Fig. 1a), with a median OS of 869 days in the CON group and not reached in the Chi group. The incidence of NRM was similar between the Chi and CON groups (5.5 vs. 16.4%, P = 0.211, Fig. 2b). The 2-year OS for T-ALL patients was similar in both groups (80.8 vs. 71.2%, P = 0.316, Fig. 1c). For patients with T-LBL, the Chi group has a better 2-year OS compared to the CON group (85.7 vs. 44.4%, P = 0.026, Fig. 1e). ETP-ALL and MPAL had similar biological characteristics, immunophenotypes, and poor outcomes [25, 26]. In our study, they were incorporated into the same group. There was a trend towards better OS in the Chi group compared to the CON group for patients with ETP-ALL and MPAL (83.3 vs. 46.9%, P = 0.244, Fig. 1g). Despite being not statistically significant, patients with MRD positive before HSCT in Chi group exhibited an advantage in 2-year OS (75.0 vs. 24.1%, P = 0.070). The univariate analysis of OS was shown in Table 3. In multivariate analysis, chidamide combined with mBuCy showed a significant association with higher OS for all patients (HR 0.032, 95%CI, 0.11–0.95; P = 0.040), while grade III-IV aGVHD (HR 5.19, 95%CI, 2.22–12.10; P < 0.001), MRD positive before HSCT (HR 3.77, 95%CI, 1.66–8.57; P = 0.002), and non-CR status of primary disease (HR 3.74, 95%CI, 1.46–9.61; P = 0.006) was associated with a lower OS (Table 4).

Table 3

Univariate analysis
Variable	HR (95%CI)	To LFS P value	HR (95%CI)	To OS P value
Conditioning regimen (Chi + mBuCy vs mBuCy)	0.38 (0.16,0.91)	0.029	0.32 (0.11,0.96)	0.042
Diagnosis
T-ALL	1		1
T-LBL	1.16 (0.56,2.39)	0.690	1.37 (0.62,3.02)	0.439
ETP-ALL	2.12 (1.00,4.52)	0.051	1.94 (0.79,4.76)	0.149
T/M MPAL	1.27 (0.48,3.36)	0.632	1.20 (0.40,3.58)	0.751
Gender (Female vs male)	1.80 (0.96,3.38)	0.069	1.57 (0.77,3.21)	0.215
Age > 35 years (Yes vs No)	1.05 (0.55,1.98)	0.891	1.00 (0.48,2.06)	0.985
WBC > 100 ×10⁹/L> (Yes vs No)	0.50 (0.22,1.12)	0.093	0.81 (0.36,1.82)	0.607
Complex karyotype (Yes vs No)	1.20 (0.58,2.46)	0.638	1.45 (0.66,3.17)	0.358
Status of primary disease
CR1	·1		1
≥CR2	2.20 (1.00,4.84)	0.049	1.73 (0.64,4.71)	0.283
non-CR	4.25 (1.99,9.02)	0.000	4.71 (1.81,12.30)	0.002
MRD positive before HSCT (Yes vs No)	2.19 (1.21,3.97)	0.010	3.20 (1.66,6.18)	0.001
Donor type
haplo	1		1
SIB	1.18 (0.42,3.32)	0.758	1.84 (0.71,4.79)	0.213
URD	0.75 (0.32,1.80)	0.523	0.60 (0.20,1.76)	0.353
Donor-recipient gender match (Yes vs No)	1.17 (0.64,2.14)	0.621	0.95 (0.48,1.86)	0.885
Stem cell source (PBSC + BM vs PBSC)	0.51 (0.25,1.04)	0.065	0.55 (0.24,1.22)	0.141
II-IV aGVHD (Yes vs No)	2.26 (1.22,4.17)	0.009	2.90 (1.45,5.77)	0.003
III-IV aGVHD (Yes vs No)	3.29 (1.60,6.74)	0.001	2.27 (1.96,9.28)	0.000
cGVHD (Yes vs No)	0.89 (0.49,1.62)	0.701	0.79 (0.39,1.58)	0.499
T-ALL T-cell acute lymphoblastic leukemia, T-LBL T-cell acute lymphoblastic lymphoma, ETP-ALL early T-cell precursor acute lymphoblastic leukemia, T/M MPAL T/myeloid mixed phenotype acute leukemia, HSCT hematopoietic stem cell transplantation, CR complete remission, MRD minimal residual disease, Haplo Haploidentical donors, SIB HLA-matched sibling donors, URD HLA-matched unrelated donors, PBSC peripheral blood stem cells, BM bone marrow, aGVHD acute graft-versus-host disease, cGVHD chronic graft-versus-host disease.

Table 4

Multivariate analysis
Variable	HR (95%CI)	To LFS P value	HR (95%CI)	To OS P value
Conditioning regimen (Chi + mBuCy vs mBuCy)	0.25 (0.09,0.61)	0.002	0.32 (0.11,0.95)	0.040
Diagnosis
T-ALL	1
T-LBL	1.11 (0.46,2.64)	0.822
ETP-ALL	1.31 (0.50,3.45)	0.589
T/M MPAL	1.32 (0.46,3.75)	0.606
Status of primary disease
CR1	1		1
≥CR2	2.17 (0.81,5.80)	0.123	2.20 (0.88,5.40)	0.092
non-CR	3.16 (1.22,8.17)	0.018	3.74 (1.46,9.61)	0.006
MRD positive before HSCT (Yes vs No)	2.04 (0.97, 4.28)	0.059	3.77 (1.66,8.57)	0.002
Stem cell source (PBSC + BM vs PBSC)	0.37 (0.46,3.75)	0.025
III-IV aGVHD (Yes vs no)	3.91(1.77,8.68)	0.001	5.19 (2.22,12.10)	0.000
CR complete remission, MRD minimal residual disease, Haplo Haploidentical donors, SIB HLA-matched sibling donors, URD HLA-matched unrelated donors, PBSC peripheral blood stem cells, BM bone marrow, aGVHD acute graft-versus-host disease, cGVHD chronic graft-versus-host disease.

Relapse and Leukemia-free survival

At the time of the last follow-up, 7 (22.7%) patients in the Chi group and 34 (41.5%) patients in the CON group relapsed after transplantation. The median time from transplantation to relapse was 255 days and 283 days, respectively. The Chi group had a significantly lower 2-year CIR than the CON group (19.0 vs. 38.4%, P = 0.030) (Fig .2a). Furthermore, compared to the CON group, the Chi group had a better 2-year LFS (76.1 vs. 51.6%, P = 0.027, Fig. 1b). For patients with T-ALL, 2-year LFS was similar between Chi and CON group (80.8 vs. 62.6%, P = 0.100, Fig. 1d), while no difference was found between two groups for patients with ETP-ALL or T/M MPAL (66.7 vs. 21.7%, P = 0.333, Fig. 1h). For patients with T-LBL, the Chi group has a better 2-year LFS compared to the CON group (76.2 vs. 34.8%, P = 0.045, Fig. 1f). Despite being not statistically significant, patients with MRD positive before HSCT in Chi group exhibited an advantage in 2-year LFS (75.0 vs. 18.6%, P = 0.068). The univariate analysis of LFS was shown in Table 3. In multivariate analysis, chidamide combined with mBuCy (HR 0.25; 95%CI, 0.09–0.61; P = 0.002), and stem cells source of bone marrow stem cells combined with peripheral blood stem cells (PBSC + BM) (HR 0.37, 95%CI, 0.46–8.68; P = 0.025) showed a significant association with a higher LFS, while grade III-IV aGVHD (HR 3.91, 95%CI, 1.77–8.68; P = 0.001) and non-CR status of primary disease (HR 3.16, 95%CI, 1.22–8.17; P = 0.018) was associated with a lower LFS (Table 4).

Despite HSCT being a reliable treatment option, T-ALL/LBL is often accompanied by a dismal prognosis, with a high likelihood of post-transplant relapse. In this study, the combination of chidamide and mBuCy conditioning regimen improves the survival of patients without increasing the incidence of transplant-related mortality.

The possible mechanisms for chidamide to improve the mBuCy regimen efficacy may include: 1) Chidamide has a direct anti-leukemic effect: chidamide can block the cell cycle at the G0/G1 phase and induce apoptosis by activating the endogenous apoptotic signaling pathways simultaneously[27]. 2) Chidamide has a synergistic effect in combination with chemotherapy, especially the alkylating agent busulfan: preclinical studies had found that HDAC inhibitors lead to a more relaxed chromatin structure through chromatin remodeling, particularly hyperacetylation of lysine residues in the histone tails, which facilitates the expression of tumor suppressor genes as well as the action of chemotherapy [28–31]. 3) The poor prognosis of DT-negative T-ALL patients was associated with abnormal DNA aggregation leading to drug resistance (e.g. VP16, MTX)[32, 33], and chidamide may be able to overcome conventional chemotherapy resistance based on its chromatin-releasing activity. 4) Chidamide combined with chemotherapy regimens can effectively decrease MRD in T-ALL patients with NOTCH1 mutation[21].

For T-ALL/LBL, especially high risk, a large portion of post-transplant relapse is due to failure to effectively eliminate MRD in bone marrow or extramedullary disease. Intensified conditioning regimens are expected to improve this situation. Our study confirmed that adding chidamide to the mBuCy regimen significantly attenuated the CIR without increasing the incidence of NRM. As a result, the patients who received the chi-intensified regimen achieved a better 2-year LFS compared to those who received the mBuCy conditioning regimen. Multivariate analysis also suggested that the Chi regimen was associated with superior OS and LFS. Currently, TBI-based regimens are more recommended than chemo-based regimens for conditioning of T-ALL[34, 35]. Compared to the TBI-based conditioning regimen, a report from the acute leukemia working party of EBMT, our outcomes displayed a higher 2-year OS (80.8 vs. about 60%). Compared with the conventional chemo-based regimen (iv Bu-Cy and oral Bu-Cy), the survival difference was more significant (80.8 vs. about 30%) [35]. TBI-based regimens have advantages for the clearance of extramedullary disease, and in our study, two patients who still with extramedullary disease before transplantation both experienced extramedullary relapse and died after transplantation. There were four patients with MRD positive before transplantation in the Chi group and all were diagnosed with T-ALL, one patient died of relapse 329 days after transplantation, and the remaining three patients continued in leukemia-free survival. Compared to the mBuCy group, the MRD-positive patients in the Chi group exhibited an advantage in LFS and OS (75.0 vs. 18.6%, 75.0 vs. 24.1%, respectively), which is consistent with previous research[21]. Hence, from the preliminary favorable results, T-ALL/LBL patients without extramedullary infiltration before transplantation may benefit from this chi-intensified regimen, especially for those with positive MRD. Unfortunately, for ETP-ALL and T/M MPAL, compared to a previous study in our center, no significant difference was seen in the OS and LFS[25]. Three patients with ETP-ALL or MPAL experienced relapse in the Chi group. One patient with MPAL died soon after relapse, and two patients with ETP-ALL prolonged survival with reinduction therapy and radiotherapy. As a high-risk subtype in T-ALL/LBL[2], ETP-ALL does not seem to benefit from the Chi-intensified conditioning regimen.

Two previous research have shown that chidamide had little toxicities in the autologous stem cell transplantation of non-Hodgkin's lymphomas (chidamide 30mg/day orally on days − 7, -4, 0, + 3, and chidamide 30mg/day orally on days − 7, -4, + 1, +3)[22, 36]. In our study (chidamide 15mg/day orally on days − 12, -9, -7, -5 for haploidentical donors and chidamide 15mg/day orally on days − 11, -9, -7, -5 for HLA match siblings or unrelated donors), despite the Chi group being associated with a higher incidence of elevation in γ-glutamyltransferase, it did not result in fatal or severe toxicity when compared to the mBuCy regimen, and liver dysfunction all had been resolved after symptomatic treatment. Considering SAEs after transplantation were comparable between the two groups, we hold that this regimen is relatively safe and manageable.

It is acknowledged that there are some limitations in our study. Our evaluation was based on a retrospective analysis of a smaller sample size. Additionally, patient selection bias may have arisen during the enrollment. We also recognized that the cytotoxicity and efficacy of chidamide are influenced by the dosage regimen (timing, frequency, and dose), necessitating further optimization. To confirm our results, we anticipate conducting future prospective randomized controlled trials on a larger scale.

To our knowledge, this is the first study to combine chidamide into a conditioning regimen for allo-HSCT in T-ALL/LBL, and the preliminary results are encouraging. Our study suggests that compared with standard mBuCy regimens, chidamide combined with mBuCy conditioning regimen may be a more effective and acceptable safety option.

T-ALL/LBL: T acute lymphoblastic leukemia/lymphoma; ETP-ALL: early T-cell precursor acute lymphoblastic leukemia; T/M MPAL: T/myeloid mixed phenotype acute leukemia; Allo-HSCT: Allogeneic hematopoietic stem cell transplantation; MRD: minimal residual disease; Haplo: Haploidentical; SIB: HLA-matched sibling; URD: HLA-matched unrelated; PBSC: peripheral blood stem cells; BM: bone marrow; GVHD: graft-versus-host disease; aGVHD: acute graft-versus-host disease; cGVHD: chronic graft-versus-host disease; OS: overall survival; LFS: leukemia-free survival; CR: complete remission; NR: no remission; PR: partial remission; NRM: non-relapse-related mortality; HDAC: histone deacetylases; HDACi: histone deacetylases inhibitor; CMV: cytomegalovirus; EBV: Epstein-Barr virus

Ethical Approval

Informed consent was obtained from all patients for being included in the study. This study was in accordance with the Helsinki Declaration and approved by the ethics committee of the First Affiliated Hospital of Soochow University (retrospective ethics review number:2023-339).

Funding

This work was supported by research grants from National Natural Science Foundation of China (82070162), Frontier Clinical Technical Project of Suzhou Science and Technology plan (SKY2022001), Bethune Charitable Foundation (BCF-IBW-XY-20220930-13), Suzhou diagnosis and treatment project of Clinical Key Diseases (LCZX202201), China International Medical Foundation (Z-2018-31-2102-4), Boxi clinical research project of The First Affiliated Hospital of Soochow University (BXLC005), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Competing Interests

The authors declare that they have no competing interests.

Author Contributions

XWT, B.A. and DPW designed the study. XWT, HPD, ZL, YMZ, MYL, SFC, WC, JY, JC, ANS, HYQ, SNC, and XMZ selected and treated patients and contributed data. XQC and QYC analyzed the data and wrote the article. QYC, ZL, and YJM critically reviewed the article. All authors read and approved the final version of the article.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author details

¹National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. ²Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China. ³Department of Dermatology, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, China. ⁴ Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United states.

Guru MG, Pondaiah SK, Abedin S, Atallah E. Incidence and survival of t-cell acute lymphoblastic leukemia in the united states. Leuk Lymphoma 2019;60(5):1171-8. https://doi.org/10.1080/10428194.2018.1522442.
Jain N, Lamb AV, O'Brien S, Ravandi F, Konopleva M, Jabbour E, et al. Early t-cell precursor acute lymphoblastic leukemia/lymphoma (etp-all/lbl) in adolescents and adults: a high-risk subtype. Blood 2016;127(15):1863-9. https://doi.org/10.1182/blood-2015-08-661702.
Attarbaschi A, Mann G, Dworzak M, Wiesbauer P, Schrappe M, Gadner H. Mediastinal mass in childhood t-cell acute lymphoblastic leukemia: significance and therapy response. Med Pediatr Oncol 2002;39(6):558-65. https://doi.org/10.1002/mpo.10164.
Deangelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, et al. Nelarabine induces complete remissions in adults with relapsed or refractory t-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: cancer and leukemia group b study 19801. Blood 2007;109(12):5136-42. https://doi.org/10.1182/blood-2006-11-056754.
Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia 2010;24(11):1844-51. https://doi.org/10.1038/leu.2010.202.
Tian H, Xu Y, Liu L, Yan L, Jin Z, Tang X, et al. Comparison of outcomes in mixed phenotype acute leukemia patients treated with chemotherapy and stem cell transplantation versus chemotherapy alone. Leuk Res 2016;45:40-6. https://doi.org/10.1016/j.leukres.2016.04.002.
Kawada H, Yoshimitsu M, Nakamura D, Arai A, Hayashida M, Kamada Y, et al. A retrospective analysis of treatment outcomes in adult t cell leukemia/lymphoma patients with aggressive disease treated with or without allogeneic stem cell transplantation: a single-center experience. Biol Blood Marrow Transplant 2015;21(4):696-700. https://doi.org/10.1016/j.bbmt.2014.12.020.
Yu J, Ge X, Luo Y, Shi J, Tan Y, Lai X, et al. Incidence, risk factors and outcome of extramedullary relapse after allogeneic hematopoietic stem cell transplantation in patients with adult acute lymphoblastic leukemia. Ann Hematol 2020;99(11):2639-48. https://doi.org/10.1007/s00277-020-04199-9.
Kamiunten A, Sekine M, Kameda T, Akizuki K, Tahira Y, Shide K, et al. Outcome of allogeneic hematopoietic cell transplantation in patients with adult t-cell leukemia. Hematol Oncol 2018;36(4):651-5. https://doi.org/10.1002/hon.2549.
Mcmahon CM, Luger SM. Relapsed t cell all: current approaches and new directions. Curr Hematol Malig Rep 2019;14(2):83-93. https://doi.org/10.1007/s11899-019-00501-3.
Kato K, Uike N, Wake A, Yoshimitsu M, Tobai T, Sawayama Y, et al. The outcome and characteristics of patients with relapsed adult t cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation. Hematol Oncol 2019;37(1):54-61. https://doi.org/10.1002/hon.2558.
Candoni A, Lazzarotto D, Ferrara F, Curti A, Lussana F, Papayannidis C, et al. Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory t-cell acute lymphoblastic leukemia/lymphoma. A campus all study. Am J Hematol 2020;95(12):1466-72. https://doi.org/10.1002/ajh.25957.
Kamiunten A, Sekine M, Kameda T, Akizuki K, Tahira Y, Shide K, et al. Outcome of allogeneic hematopoietic cell transplantation in patients with adult t-cell leukemia. Hematol Oncol 2018;36(4):651-5. https://doi.org/10.1002/hon.2549.
Chen H, Qin Y, Yang J, Liu P, He X, Zhou S, et al. Dismal outcome of relapsed or primary refractory adult t-cell lymphoblastic lymphoma: a retrospective study from china. Asia Pac J Clin Oncol 2022;18(2):e87-95. https://doi.org/10.1111/ajco.13562.
Zhang XH, Chen J, Han MZ, Huang H, Jiang EL, Jiang M, et al. The consensus from the chinese society of hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update. J Hematol Oncol 2021;14(1):145. https://doi.org/10.1186/s13045-021-01159-2.
Zhao XF, Mao XF, Wan DM, Liu W. Modified busulfan and cyclophosphamide conditioning regimen for allogeneic hematopoietic stem cell transplantation in the treatment of patients with hematologic malignancies. Transplant Proc 2014;46(5):1531-5. https://doi.org/10.1016/j.transproceed.2014.02.023.
Suresh PS, Devaraj VC, Srinivas NR, Mullangi R. Review of bioanalytical assays for the quantitation of various hdac inhibitors such as vorinostat, belinostat, panobinostat, romidepsin and chidamine. Biomed Chromatogr 2017;31(1). https://doi.org/10.1002/bmc.3807.
Shi Y, Jia B, Xu W, Li W, Liu T, Liu P, et al. Chidamide in relapsed or refractory peripheral t cell lymphoma: a multicenter real-world study in china. J Hematol Oncol 2017;10(1):69. https://doi.org/10.1186/s13045-017-0439-6.
Cao HY, Li L, Xue SL, Dai HP. Chidamide: targeting epigenetic regulation in the treatment of hematological malignancy. Hematol Oncol 2022. https://doi.org/10.1002/hon.3088.
Gao S, Li X, Zang J, Xu W, Zhang Y. Preclinical and clinical studies of chidamide (cs055/hbi-8000), an orally available subtype-selective hdac inhibitor for cancer therapy. Anticancer Agents Med Chem 2017;17(6):802-12. https://doi.org/10.2174/1871520616666160901150427.
Xi M, Guo S, Bayin C, Peng L, Chuffart F, Bourova-Flin E, et al. Chidamide inhibits the notch1-myc signaling axis in t-cell acute lymphoblastic leukemia. Front Med 2022;16(3):442-58. https://doi.org/10.1007/s11684-021-0877-y.
Ji J, Liu Z, Kuang P, Dong T, Chen X, Li J, et al. A new conditioning regimen with chidamide, cladribine, gemcitabine and busulfan significantly improve the outcome of high-risk or relapsed/refractory non-hodgkin's lymphomas. Int J Cancer 2021;149(12):2075-82. https://doi.org/10.1002/ijc.33761.
Tang X, Valdez BC, Ma Y, Zhang Q, Qu C, Dai H, et al. Low-dose decitabine as part of a modified bu-cy conditioning regimen improves survival in aml patients with active disease undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2021;56(7):1674-82. https://doi.org/10.1038/s41409-021-01238-5.
Xu GF, Liu LM, Wang M, Zhang ZB, Xie JD, Qiu HY, et al. Treatments of ph-like acute lymphoblastic leukemia: a real-world retrospective analysis from a single large center in china. Leuk Lymphoma 2022;63(11):2652-62. https://doi.org/10.1080/10428194.2022.2090550.
Liu S, Cui Q, Dai H, Song B, Cui W, Xue S, et al. Early t-cell precursor acute lymphoblastic leukemia and t/myeloid mixed phenotype acute leukemia possess overlapping characteristics and both benefit from cag-like regimens and allogeneic hematopoietic stem cell transplantation. Transplant Cell Ther 2021;27(6):481. https://doi.org/10.1016/j.jtct.2021.02.032.
Noronha EP, Marques L, Andrade FG, Sardou-Cezar I, Dos SF, Zampier C, et al. T-lymphoid/myeloid mixed phenotype acute leukemia and early t-cell precursor lymphoblastic leukemia similarities with notch1 mutation as a good prognostic factor. Cancer Manag Res 2019;11:3933-43. https://doi.org/10.2147/CMAR.S196574.
Gong K, Xie J, Yi H, Li W. Cs055 (chidamide/hbi-8000), a novel histone deacetylase inhibitor, induces g1 arrest, ros-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 2012;443(3):735-46. https://doi.org/10.1042/BJ20111685.
Rosato RR, Grant S. Histone deacetylase inhibitors: insights into mechanisms of lethality. Expert Opin Ther Targets 2005;9(4):809-24. https://doi.org/10.1517/14728222.9.4.809.
Secrist JP, Zhou X, Richon VM. Hdac inhibitors for the treatment of cancer. Curr Opin Investig Drugs 2003;4(12):1422-7.
Valdez BC, Murray D, Nieto Y, Li Y, Wang G, Champlin RE, et al. Synergistic cytotoxicity of the dna alkylating agent busulfan, nucleoside analogs, and suberoylanilide hydroxamic acid in lymphoma cell lines. Leuk Lymphoma 2012;53(5):973-81. https://doi.org/10.3109/10428194.2011.634043.
Valdez BC, Nieto Y, Murray D, Li Y, Wang G, Champlin RE, et al. Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-dna alkylating agents in lymphoma cell lines. Exp Hematol 2012;40(10):800-10. https://doi.org/10.1016/j.exphem.2012.06.001.
Xiao H, Wang S, Tang Y, Li S, Jiang Y, Yang Y, et al. Absence of terminal deoxynucleotidyl transferase expression in t-all/lbl accumulates chromosomal abnormalities to induce drug resistance. Int J Cancer 2023;152(11):2383-95. https://doi.org/10.1002/ijc.34465.
Zhou Y, Fan X, Routbort M, Cameron YC, Singh R, Bueso-Ramos C, et al. Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult t-lymphoblastic leukemia/lymphoma. Mod Pathol 2013;26(10):1338-45. https://doi.org/10.1038/modpathol.2013.78.
Niu J, Chen Z, Gao J, Qiu H, Wan L, Wang Y, et al. Total body irradiation-based conditioning regimen improved the survival of adult patients with t-cell lymphoblastic lymphoma after allogeneic peripheral blood stem cell transplantation. Cell Transplant 2022;31:73800550. https://doi.org/10.1177/09636897221108890.
Cahu X, Labopin M, Giebel S, Aljurf M, Kyrcz-Krzemien S, Socie G, et al. Impact of conditioning with tbi in adult patients with t-cell all who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of ebmt. Bone Marrow Transplant 2016;51(3):351-7. https://doi.org/10.1038/bmt.2015.278.
Xia Y, Wang L, Ding K, Wu J, Yin H, Hu M, et al. Chidamide-beac plus autologous stem cell transplantation in high-risk non-hodgkin lymphoma: a phase ii clinical trial. Chin Med J (Engl) 2023;136(12):1491-3. https://doi.org/10.1097/CM9.0000000000002636.

No competing interests reported.

Download PDF

Journal Publication

published 28 Nov, 2023

Read the published version in Blood →

Version 1

posted

You are reading this latest preprint version

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Patients

Conditioning regimens

Graft-versus-host disease prophylaxis

Definitions and statistical methods

Results

Patient enrollment and characteristics

Engraftment and GVHD

Safety

Non-relapse related mortality and Overall Survival

Relapse and Leukemia-free survival

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1