To the editor:
Sickle cell anemia and β-thalassemia remain the most common human genetic disorders worldwide. High fetal hemoglobin (HbF) levels are correlated with reduced morbidity and mortality in both diseases. Based on this observation, recent studies provide new insight into the molecular mechanisms of the hemoglobin switching to induce the HbF production in adult hemopoietic cells as a promising therapeutic approach to ameliorate the severity of these two disorders.1,2
A strong support to such novel approaches comes from recent clinical observations carried out by our group: in 3 patients affected by β-hemoglobin disorders the reactivation of HbF synthesis has been documented after bone marrow transplantation (BMT) failure and autologous reconstitution.
At the first, we observed 2 β°-thalassemia major cases who were prepared for BMT according to protocol 263 : the first thalassemic patient, recently reported,4 rejected at +40 days after BMT and the second at +116 days after transplant. The autologous recovery was documented by the DNA molecular analysis that detected 0% residual donor cells in both cases.
Transfusion therapy was required to support anemia until +118 and +162 days after transplant in the first and second cases, respectively. Afterward, the Hb levels were steadily more than 11.8 and 10.2 g/dL, respectively, without the use of transfusion support and the Hb electrophoresis revealed HbF 99.8% in both cases. The engraftment tests were repeated in both cases during the follow-up to ascertain whether a minimal amount of donor cells was still present in the bone marrow. The DNA tests confirmed 0% residual donor cells in the peripheral blood as well as in the bone marrowsamples of both patients. To establish whether a “fetal clone” was selected after the BMT failure, in the female patient the clonality analysis at human androgen receptor locus (HUMARA) was performed. The HUMARA assay5 showed a random X-chromosome inactivation pattern, indicating the absence of hematopoietic clonality.
As we write this at +67 and +55 months, respectively, of ongoing follow-up after graft failure, both patients maintain the sustained and full (99.8%) production of HbF and are transfusion-free (see Table 1).
Clinical and hematologic parameters in 3 patients pre-transplant and postBMT failure
| . | Patient 1 . | Patient 2 . | Patient 3 . |
|---|---|---|---|
| Sex/age* | M/18 | F/13 | M/5 |
| Disease | β°-thalassemia | β°-thalassemia | Sickle cell anemia |
| Follow-up after BMT (mo) | + 67 | + 55 | + 19 |
| Pre-BMT Hb (gr/dL) | 8.3-9.0 | 7.0-8.1 | 7.0-7.4 |
| Post-BMT Hb (gr/dL) | 11.8-13 | 10.2-10.55 | 11.4-12.3 |
| Pre-BMT HbF level (%) | 73 | 24 | 19.3 |
| Post-BMT HbF level (%) | 99.8 | 99.8 | 49.6 |
| Pre-BMT reticulocytes (%) | 4.07 | 4.09 | 10.1 |
| Post-BMT reticulocytes (%) | 6.57 | 7.95 | 3.15 |
| Pre-BMT circulating erythroblasts† (% of total nucleated cells) | 88 | 83 | 0 |
| Post-BMT circulating erythroblasts (% of total nucleated cells) | 58 | 60 | 0 |
| Pre-PMT HPLC‡ | α/non α: 2.47; %β: 0 | α/non α: 2.43; %β: 0 | α/non α: 1,1; %β: 100 β S |
| Post-BMT HPLC | α/non α: 0.97; %β: 0 | α/non α: 1.20; %β: 0 | α/non α: 1.16; β: 100 β S |
| Pre-BMT bone marrow biopsy | marked erythroid hyperplasia | marked erythroid hyperplasia | marked erythroid hyperplasia |
| Post-BMT bone marrow biopsy | mild erythroid hyperplasia | mild erythroid hyperplasia | normoblastic erythropoiesis |
| . | Patient 1 . | Patient 2 . | Patient 3 . |
|---|---|---|---|
| Sex/age* | M/18 | F/13 | M/5 |
| Disease | β°-thalassemia | β°-thalassemia | Sickle cell anemia |
| Follow-up after BMT (mo) | + 67 | + 55 | + 19 |
| Pre-BMT Hb (gr/dL) | 8.3-9.0 | 7.0-8.1 | 7.0-7.4 |
| Post-BMT Hb (gr/dL) | 11.8-13 | 10.2-10.55 | 11.4-12.3 |
| Pre-BMT HbF level (%) | 73 | 24 | 19.3 |
| Post-BMT HbF level (%) | 99.8 | 99.8 | 49.6 |
| Pre-BMT reticulocytes (%) | 4.07 | 4.09 | 10.1 |
| Post-BMT reticulocytes (%) | 6.57 | 7.95 | 3.15 |
| Pre-BMT circulating erythroblasts† (% of total nucleated cells) | 88 | 83 | 0 |
| Post-BMT circulating erythroblasts (% of total nucleated cells) | 58 | 60 | 0 |
| Pre-PMT HPLC‡ | α/non α: 2.47; %β: 0 | α/non α: 2.43; %β: 0 | α/non α: 1,1; %β: 100 β S |
| Post-BMT HPLC | α/non α: 0.97; %β: 0 | α/non α: 1.20; %β: 0 | α/non α: 1.16; β: 100 β S |
| Pre-BMT bone marrow biopsy | marked erythroid hyperplasia | marked erythroid hyperplasia | marked erythroid hyperplasia |
| Post-BMT bone marrow biopsy | mild erythroid hyperplasia | mild erythroid hyperplasia | normoblastic erythropoiesis |
Age at the moment of BMT.
Orthochromatic erythroblasts.
High-performance liquid chromatography analysis.
The third case is a sickle cell anemia patient with a pretransplant HbS level of 77.3%. The patient failed to maintain the engraft (97% at +20 days after BMT) of the aploidentical allogeneic transplant6 and the autologous recovery was documented +48 days after BMT (0% donor at the DNA molecular analysis). Nineteen months after the BMT failure, the HbF levels increased to 49.2, the HbS levels decreased to 49.6%, and the patient remains free of transfusion therapy with stable Hb level > 11.4 gr/dL and without vaso-occlusive symptoms (Table 1).
The 3 cases show that the reactivation of HbF synthesis can occur in adults and the high levels of HbF provide a therapeutic benefit to the β-disorders.
Although the mechanisms underlying the switch back to stable HbF production after BMT failure need further investigation, these cases strongly support the research efforts to reverse the hemoglobin switch and induce the HbF production in adults to treat the β-hemoglobin disorders.
Authorship
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Katia Paciaroni, MD, International Centre for Transplantation in Thalassaemia and Sickle Cell Anaemia, Mediterranean Institute of Haematology, Policlinic of “Tor Vergata” University, Viale Oxford 00152, Rome, Italy; e-mail: k.paciaroni@fondazioneime.org.
