Sequential therapy with decitabine and an XPO-1 inhibitor followed by allogeneic hematopoietic stem cell transplantation in MDS with biallelic TP53 inactivation patients : a preliminary case series

Abstract

Myelodysplastic syndrome with biallelic TP53 inactivation (MDS-biTP53) patients represents an ultra-high-risk subgroup with dismal outcomes. Even after allogeneic hematopoietic stem cell transplantation (allo-HSCT), relapse rates remain extremely high and survival is poor. This preliminary case series reports the outcomes of 8 consecutive patients with MDS-biTP53 who received a novel sequential therapy of decitabine (DAC) combined with the XPO-1 inhibitor selinexor, followed by allo-HSCT at a single center between September 2024 and December 2025. At a median follow-up of 7.3 months (95% CI, 4.2–10.4 months) from HSCT, median overall survival (OS) and relapse-free survival (RFS) were not reached. At last follow-up, 7/8 patients remained alive (OS 87.5%) and 6/8 were relapse-free (RFS 75%), with one relapse (12.5%). This patient successfully achieved a second complete remission following preemptive therapy with low-dose decitabine combined with donor lymphocyte infusion and remained in remission at the last follow-up. Two patients developed serious infections during the peritransplant period. One patient with pre-transplant intestinal colonization of carbapenem-resistant Enterobacteriaceae (CRE) ultimately died due to CRE bloodstream infection followed by intestinal graft-versus-host-disease (GVHD). Overall treatment-related toxicity was deemed manageable, and the incidence of grade III-IV acute GVHD was 25% (2/8). This preliminary study provides encouraging evidence that sequential decitabine and selinexor therapy followed by allo-HSCT may improve outcomes with acceptable toxicity in patients with ultra-high-risk MDS-biTP53. However, these findings are limited by the small sample size, relatively short follow-up, and retrospective, single-center design. Confirmation in larger prospective trials is warranted.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40164-026-00817-w.

To the Editor,

Myelodysplastic syndromes with biallelic TP53 inactivation (MDS-biTP53) represent a distinct entity with dismal outcomes. These patients respond poorly to conventional therapies—including hypomethylating agents [1], BCL-2 inhibitors [2], and immunomodulatory drugs [3] -as recently reviewed [4]. Even with allo-HSCT, median time to post-transplant relapse is only 4 to 6 months [5], with 1-year overall survival rates around 20–30% [6]. This underscores an urgent need for novel approaches to reduce relapse and improve survival.

We report a case series of 8 adult patients with NGS-confirmed MDS-biTP53 treated at our centre between September 2024 and December 2025. All patients received a sequential protocol consisting of a 2-week cytoreductive course with decitabine (20 mg/m², days 1–5) and selinexor (20 mg orally twice weekly), followed immediately by a decitabine‑based conditioning regimen and allo-HSCT. Conditioning was either DAC‑BuCy or DAC‑BF; detailed doses and schedules are in Supplementary Table S1. GVHD prophylaxis comprised anti-thymocyte globulin (ATG), calcineurin inhibitors, and short-course methotrexate. The study was approved by our Institutional Review Board (No. 0352-2026B).

Patient characteristics are detailed in Table 1. Median age at allo-HSCT was 60 years all were very high risk according to IPSS‑R/M scoring systems. Five patients had prior hypomethylating agents therapy, with only one achieving marrow complete remission (mCR). All patients achieved neutrophil engraftment (median 11 days); platelet engraftment failed in one cord blood recipient. At first post-transplant assessment (day + 30), all were in morphological remission and TP53-mutant clone negative by ddPCR.

Table 1.

Clinical characteristics of patients

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8
Age	61	59	68	52	64	58	55	63
Sex	Female	Male	Male	Male	Female	Female	Female	Male
WHO -type	IB2	IB1	IB2	IB2	IB1	IB2	IB1	IB2
TP53 mutation	c.700T > C	c.422G > A	c.587G > C, c.503 A > T, c.473G > A	c.916 C > T	c.659 A > G	c.1009 C > T	c.824G > T, c.555delC	c.375 + 1G > T
VAF of TP53 mutation	69.67%	24.19%	26.69%, 5.35%, 28.50%	82.45%	85.15%	79.0%	66.25%, 7.5%	80.85%
Combined mutation	SUZ12	no	DNMT3A	no	ASXL2 KMT2A USP9X	FANCC	PPM1D	no
Karyotype	CK	CK(17p-)	CK	CK(-17)	CK	CK	CK	CK(-17)
IPSS-R	8	7.5	7.5	8	8.5	6.5	7	8
IPSS-M	3.4	2.7	3.36	3.07	3.5	2.6	3.6	2.76
Fibrosis	yes	No	No	No	No	No	No	Yes
Treatment before transplant	AZA+CD47	AZA + Ven	AZA	AZA + Ven	DAC	NO	NO	NO
Status at transplant	PD	mCR	SD	PD	PD	SD	SD	SD
Donor type	HID(daughter)	HID(son)	HID(son)	HID(son)	HID(son)	HID(son)	HID(son)	CBD

IB, MDS with increased blasts 1; VAF, variant allele frequency; CK, complex karyotype; IPSS‑R, Revised International Prognostic Scoring System; IPSS‑M, Molecular International Prognostic Scoring System; AZA, Azacitidine; Ven, venetoclax; DAC, decitabine; PD, Progressive Disease; SD, Stable Disease; HID, haploidentical donor, CBD, cord blood donor

At a median follow‑up of 7.3 months (range 2.8‑16.7) since HSCT, median OS and RFS were not reached. Observed proportions at last follow-up were 87.5% (7/8) for OS and 75% (6/8) for RFS (Fig. 1). One patient relapsed (12.5%) but achieved a second complete remission with low-dose decitabine and donor lymphocyte infusion (DLI). One non-relapse mortality occurred due to septic shock from CRE infection and GVHD. Grade III-IV acute GVHD occurred in two patients (25%).

Fig. 1.

Transplant outcome of all patients

To our knowledge, this is the first report of sequential decitabine and selinexor followed directly by allo‑HSCT specifically for MDS‑biTP53 patients. Conventional bridge regimens, including HMA+venetoclax [7], carry risks of infection and outgrowth of resistant clones during the waiting period, yet the benefit of pre‑transplant cytoreduction in TP53-mutated MDS remains debated [8]. Our protocol eliminates this interval. Mechanistically, decitabine induces p53‑independent mitotic catastrophe in TP53‑mutant cells, while selinexor forces nuclear retention of residual tumor suppressors, partially restoring apoptosis [1, 9]. Preclinical studies show synergistic inhibition of MDS cell proliferation [10], with clinical activity reported in HMA‑refractory MDS [11]. We hypothesize that this combination enabled deeper pre‑transplant clearance of TP53‑mutant clones, and the direct transition to transplantation may have prevented adverse selection, contributing to the low relapse rate and durable molecular remissions in our cohort.

Given the small sample and retrospective design, these findings remain preliminary; nonetheless, this sequential strategy merits further investigation as a potential option for this ultra-high-risk population.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

MDS-biTP53

Myelodysplastic syndrome with biallelic TP53 inactivation

allo-HSCT

Allogeneic hematopoietic stem cell transplantation

OS

Overall survival

RFS

Relapse free survival

CIR

Cumulative incidence of relapse

NRM

Non-relapse mortality

NGS

Next-generation sequencing

GVHD

Graft-versus-host disease

ATG

Anti-thymocyte globulin

IPSS-R

International Prognostic Scoring System-Revised

IPSS-M

International Prognostic Scoring System Molecular

VAF

Variant allele frequencies

AZA

Azacitidine

CK

Complex karyotype

HCT-CI

Hematopoietic cell transplantation-specific comorbidity index

HID

Haploidentical donor

CBD

Cord blood door

DLI

Donor lymphocyte infusion

Author contributions

YLR conceived the study, analyzed data, and drafted the manuscript. WL analyzed data. YX, CM and XBH collected and interpreted the data, SSW and JJQ followed the patient. HYT reviewed the manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The single institute data from this study is available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the Institutional Review Board of The First Affiliated Hospital of Zhejiang University, School of Medicine (Approval No.: 0352-2026B). Although a waiver of informed consent was granted for the retrospective chart review, written consent for telephone follow-up had been obtained from all subjects.

Consent for publication

All authors of the manuscript have read and agreed to its content for publication.

Competing interests

The authors declare no competing interests.