Late recurrence of transfusion dependent thalassemia 30 years after transplantation

Abstract Here we report 5 cases of patients transplanted in the eighties/early nineties who experienced an unexpected, unheralded, and unexplained graft loss and thalassemia recurrence more than 30 years after transplantation. Case#1: A 16-month-old male was transplanted in 1982 (Lancet, 1982), conditioned with dimethyl busulfan and cyclophosphamide. Donor: HLA-identical sister without thalassemia trait. The post-transplant course was successful. Following the initial publication, no further data were available until the patient presented in 2014 (age 32 years) with severe anemia (Hb 6.5 g/dL) and 5% donor chimerism (STR). The patient resumed regular red blood cell transfusions and was later lost to follow-up. Case#2: A 3.7-year-old male underwent HCT in 1985. Donor: HLA-identical brother with thalassemia trait. Engraftment was initially monitored indirectly through blood group typing. Starting in 2012, a progressive and gradual decline in Hb levels was observed, reaching 6.5 g/dL by July 2016 (day +11,402). At that time, STR analysis revealed 19% donor chimerism. The patient resumed regular transfusions. Donor chimerism continued to decline, reaching 16% by September 2019. He remains on regular transfusions and iron chelation therapy. Case#3: A 3.6-year-old female was transplanted in 1994. Donor: HLA-identical sister with thalassemia trait. The transplant course was uneventful, with full donor chimerism documented in 2010. Subsequently, Hb levels declined to 9 g/dL, and donor chimerism dropped to 25% by 2016. A progressive decline in both Hb and donor chimerism continued, reaching 7.5 g/dL and 17%, respectively, by July 2024 (day +11,046), at which point regular transfusions were resumed. Case#4: A 2.5-year-old female was transplanted in 1994. Donor: HLA-identical sister. In the first two years after transplant a complete chimerism was demonstrated by repeated molecular tests. In April 2021 (day +9,720, age 29 years) concomitant with a second pregnancy a decline in Hb was observed and transfusions resumed. Chimerism was investigated later in December 2022 demonstrating 26% donor cells. Test was repeated in March and confirmed 20% donor cells and transfusion dependence was diagnosed. She underwent a second transplant on October 2023 from the same donor and is actually alive and well. Case#5: A 26-year-old male with combined heterozygosis sickle cell disease/thalassemia conditioned in 1990. Donor: HLA-identical sister with thalassemia trait. He remained clinically well with full donor engraftment for 5 years, with no detectable HbS. In late 2024, a decline in hemoglobin levels was noted. In January 2025 (day +12,600), hemoglobin electrophoresis revealed 20% HbS and 7% HbF. FISH analysis showed 61% Y/X metaphases, and blood typing indicated 80% A+ and 20% O+ red cells. The patient is currently under watchful waiting. Limited data are available on the long-term (30 years) survival of allogeneic hematopoietic engraftment, regardless of the underlying disease. Patients with TDT who underwent transplantation in the 1980s represent a unique natural model to assess the long-term potential of transplanted hematopoietic stem cells to sustain hematopoiesis over several decades. All cases reported here share the common feature of having undergone transplantation in the eighties/early nineties. All but case#1 were conditioned with the classic Busulfan-Cyclophosphamide myeloablative (mostly oral) regimen and received an HLA identical sibling donor. None received anti-thymocyte globulin or had chronic GvHD. All presented optimal QoL. In no case was a clear trigger of immunological rejection in the months preceding recurrence of transfusion dependence. When follow-up was available, recurrence was characterized by a gradual replacement of the allogeneic graft through a phase of mixed chimerism with final re-emergence of recipient hematopoiesis. This process manifested solely as anemia (or recurrence of HbS), without any platelets and white blood cells drop. These reported cases represent more than isolated occurrences. These observations raise the possibility of long-term exhaustion of allogeneic engraftment and, simultaneously, support the concept of the persistence or “immortality” of autologous thalassemic hematopoietic stem cells, which may remain quiescent for decades following myeloablative conditioning. Systemic observation in the unique cohort of thalassemia patients is warranted