Long-Term Outcomes and Late Complications of Allogeneic Stem Cell Transplant with CD34+ Positive Selection in Adults with Acute Leukaemia and Myelodysplastic Syndrome: A Single-Centre Study

INTRODUCTION:

Ex vivo T cell depletion (TCD) by CD34+ selection (CD34+s) significantly reduces acute and chronic graft-versus-host disease (GVHD) without increasing relapse in hematological malignancies but raises infection rates. Long-term outcomes and late complications of this approach are under-documented.

METHODS:

We retrospectively analyzed data from 2016 to 2022 for patients undergoing CD34+s allogeneic stem cell transplant (alloSCT) at Vall d’Hebron Hospital, Spain, for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS), with a minimum 12-month follow-up. The CD34+s alloSCT platform combined ex vivo CD34+s and in vivo TCD with ATG 5-7.5 mg/kg. Conditioning regimens included myeloablative (MAC) with total body irradiation 12 Gy, thiotepa 10 mg/kg, and cyclophosphamide 120 mg/kg (TBI-TT-Cy) for fit, young patients (≤50 years) and reduced intensity (RIC) with fludarabine 125 mg/m², busulfan 9.6 mg/kg, and melphalan 140 mg/m²(Flu-Bu-Mel). No post-transplant immunosuppressive therapy was planned. Informed consent was obtained from all patients. We used Stata/BE 17.0 for univariate analysis of categorical and continuous variables, bivariate analysis with classical hypothesis tests, and survival analysis with Kaplan-Meier and log-rank tests.

RESULTS:

Median follow-up of the study was 29.3 months [0.8-97.4]. Eighty-eight patients were included: 53.4% female, median age 50.5 [18-71]. Most had AML (62.5%), followed by ALL (18.2%) and MDS (19.3%), with high-risk disease (70.5%) and 41.9% with more than one prior treatment. Unrelated donors were used in 70.4%, with 59% full match. MAC was used in 48.9%. Previous comorbidities: 14.8% respiratory, 13.7% endocrine, 5.7% autoimmune, 4.6% chronic liver, 2.27% chronic kidney, and one cardiovascular case. The median HCT-CI score was 2 [0-9].

Two patients experienced graft failure (2.3%, one primary and one secondary), with median engraftment at 12 days [8-22], similar in both MAC (11) and RIC (12). Acute GVHD occurred in 23.9% (4.5% grade ≥3) and chronic GVHD in 3.4% (only one severe). Infections were frequent: 55.4% had ≥3 infections requiring antibiotics or admission in one year, 61.4% had CMV reactivation, 17% EBV requiring rituximab, 18.2% BK virus, and 9% adenovirus.

Late complications in 49 patients alive >1 year post-transplant included gonadal dysfunction (23.8% males, 28% females), thyroid disease (14%), respiratory disease (28.6%), osteopenia (36.7%), osteoporosis (20.4%), cataracts (12.2%) and iron overload (12.2%). Secondary malignancies were noted in 12.2% (4 solid tumors, 2 hematological). Avascular necrosis was not found.

New cardiovascular risk factors were seen in 59.1% of the patients. Dyslipidemia was the most common (18%), followed by metabolic syndrome (16.3%), hypertension (14%), type 2 diabetes (8.1%), and abnormal echocardiogram (8.1%). Heart failure was diagnosed in only one patient, and none had ischemic cardiac disease.

Engraftment was sustained, with only 20% requiring hematopoietic support at 12 months (18% erythropoietin (EPO), 8% G-CSF, 8% eltrombopag), reducing to 6.4% at 2 years (needing only EPO). Lymphopenia was present in 34% of patients at 12 months and decreased over time to 6.4% at 2 years, 2.5% at 3 years, and 0% at 4 years. Immune reconstitution steadily improved. Over the same time points (12 months, 2 years, 3 years, and 4 years), low CD4+ lymphocytes dropped from 62% to 26.7%, 14.3%, and 0%. Low NK cells decreased from 6% to 4.4% and 0%. CD19 lymphopenia fell from 20% to 11.1% and 0%.

Female hypogonadism was significantly higher in MAC (93.3%) vs RIC (6.7%) (p=0.008). No other significant differences were found between MAC and RIC.

Overall survival (OS) was 55% at 3y, higher in MAC (65.1%) than RIC (45.2%) (p=0.02). Relapse occurred in 27.2% of patients, with 70.4% still in complete remission. Relapse was the most common cause of death, followed by infections. Progression-free survival (PFS) at 3y was 69.9% (MAC 75.9% vs. RIC 63.3%, p=0.25). Non-relapse mortality (NRM) was 23.4% at 3y, higher in RIC (30.6% vs. 15.9%, p=0.04). GVHD-free survival was 93.9% at 3y (100% RIC vs. 89.6% MAC, p=0.14). GVHD and relapse-free survival (GRFS) was 64% at 3y (MAC 65%, RIC 63.3%, p=0.63).

CONCLUSION:

The CD34+s alloSCT platform offers good long-term outcomes with low GVHD rates and high GRFS, indicating a good quality of life for survivors one year post-transplant.