Sickle cell disease is the most common genetic disorder in the Eastern Mediterranean region where our transplant center is located. Today, adult patients with sickle cell disease can also be successfully treated with allogeneic hematopoietic stem cell transplantation. Bone marrow necrosis is a rare and serious clinical condition. Herein, we present this complication for the first time in the literature, which developed in the course of allogeneic hematopoietic stem cell transplantation and was successfully managed with additional bone marrow support. The recognition, prevention, and management of this rare and potentially fatal complication, bone marrow necrosis, are vitally important, especially in regions with high prevalence of sickle cell disease.
Key words : Bone marrow failure, Hematopoietic stem cell transplantation, Hemoglobin S disease
Bone marrow necrosis (BMN) is a rare clinical condition and was first described in the autopsy of a patient with sickle cell disease (SCD).1 Bone marrow necrosis is defined as the detection of poorly defined necrotic cells in an amorphous eosinophilic background with the cortical bone preserved.2 The pathophysiology of BMN is not clear. Disruption of bone marrow microcirculation and cell damage caused by hypoxic condition are thought to be the underlying common features. In 90% of cases, the primary cause is malignant diseases. Sickle cell disease has been defined as the underlying disease in only 2% of the cases.3
Adult patients with SCD are susceptible to the complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a result of endothelial activation, inflammation, and tissue damage.4 Recently, allo-HSCT has been successfully applied in adult SCD cases. Here, we present an adult patient with SCD who developed extensive BMN during the administration of an allo-HSCT conditioning regimen and whose treatment was successfully managed.5,6
A 25-year-old male patient with a diagnosis of heterozygous combination of hemoglobin S and β-thalassemia was hospitalized for allo-HSCT from a fully matched HLA-compatible donor as a result of frequent painful crises and allo-immunization. On physical examination, his general condition was good, the skin was pale, and the conjunctivae were subicteric. The spleen was 3 cm palpable below the rib. Laboratory findings were as follows: hemoglobin level of 12 g/dL, leukocyte level of 5.6 × 103/μL, and platelet level of 91 × 103/μL. Electrophoresis results showed 5.8% hemoglobin A2, 4.6% hemoglobin F, 79.2% hemoglobin S, and 10.4% hemoglobin A. After red blood cell exchange had been applied, a nonmyeloablative conditioning regimen (150 mg/m2 fludarabine, 3.2 mg/kg busulfex, 20 mg/kg rabbit antithymocyte globulin-Fresenius [rATG-F], 29 mg/kg cyclophosphamide, 200 cGy total body irradiation, 4 mg sirolimus, 2000 mg mycophenolate mofetil, 100 mg/kg cyclophosphamide) was initiated.
Widespread bone pain that was difficult to control with narcotic analgesics occurred from day 2 of the conditioning regimen. During the following days, the patient had a fever reaching 40 °C. Peripheral blood-derived stem cell product was infused at the scheduled time.
Twenty days after transplantation, bone marrow aspiration was evaluated due to the persistence of clinical problems and pancytopenia and the appearance of leuko-erythroblasts in peripheral blood smear. A gelatinous basophilic material was aspirated (Figure 1a). Morphologically, the cells were degenerated, so their structure could not be identified (Figure 1b). Findings of bone marrow biopsy performed 1 month later were compatible with diffuse BMN (Figure 2). After transplant, although the patient had a complete donor chimerism for total cells, clinical findings and pancytopenia did not improve despite all supportive treatments. From clinical and laboratory data findings, we concluded that the patient had poor graft function due to BMN. Therefore, bone marrow collected from the original donor was infused after 70 days, with administration of rATG-F 5 mg/kg at -1 day.
On follow-up, 50 mg/day of eltrombopag was given as supportive therapy. After 2 months, the patient was clinically stable. Acute or chronic graft-versus-host disease (GVHD), graft rejection, or severe infectious complications did not develop.
After bone marrow infusion, on day 245, hemoglobin level was 13.2 g/dL, leukocyte count was 4.0 × 103/μL, platelet count was 107 × 103/μL, and hemoglobin electrophoresis revealed 2.5% hemoglobin A2, 0% hemoglobin F, 0% hemoglobin S, and 97.3% hemoglobin A.
At month 12, immunosuppressive drugs were discontinued. The patient has remained disease free at 27 months.
Bone marrow necrosis appears to be associated with various clinical conditions, including malignant diseases, infections, autoimmune diseases, chemotherapy, disseminated intravascular coagulation, anorexia nervosa, antiphospholipid syndrome, and SCD.1,2,7-10 Bone marrow necrosis is rarely encountered in clinical practice, with an incidence that varies between 0.3% and 37%.2 Although the first case of BMN was reported in a patient with SCD, BMN reported in SCD patients is extremely rare.3 A possible reason for the difficulty in defining this relationship is that bone marrow examination has not been performed widely during the SCD crisis.11,12 Charache and Page pointed out that, in 1 of 6 patients with SCD during the painful crisis, a certain rate of bone marrow necrosis develops, and generally these patients completely recover.13 Tsitsikas and associates paradoxically found that patients with mild clinical phenotypes had a higher risk of this serious complication.14
Sickle cell disease is the most common genetic disease in the Eastern Mediterranean region. Because the incidence of the disease is 9.6%, it is an important medical and social problem in the region.15
The clinical course of the patient presented here was mild in terms of the frequency of vasoocclusive attacks before allo-HSCT. Bone pain occurring in the early period of allo-HSCT was initially evaluated as an acute painful crisis. However, because of the prolonged painful condition and cytopenias, bone marrow biopsy was performed and diffuse BMN was diagnosed. To correct the bone marrow microenvironment, it was decided to perform a bone marrow infusion while in an immunosuppressive state with only rATG-F administration.
This is the first case that reported development of BMN in a patient while the patient was receiving a pretransplant conditioning regimen, with correction with cellular therapy. Today, allo-HSCT is successfully performed by our team in adult patients with SCD up to the age of 50 years. In transplants from HLA fully matched siblings, without graft rejection, the cumulative incidence is <5% for grade III to IV acute GVHD and 0% for extensive chronic GVHD, with nonrelapsed mortality of 0%.5,6
Our experience showed that BMN may also occur during allo-HSCT. This catastrophic situation appears to be correctable with additional bone marrow product collected from the same donor.
DOI : 10.6002/ect.2021.0170
From the 1Department of Hematology, Adana Adult Bone Marrow Transplantation Center, Baskent University, Ankara; the 2Department of Physiology, Adana Adult Bone Marrow Transplantation Center, Baskent University, Ankara; the 3Department of Family Medicine, Çukurova University Hospital, Adana; and the 4Department of Pathology, Baskent University Hospital, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Hakan Ozdogu, Baskent University, Department of Hematology, Adana Adult Bone Marrow Transplantation Center, 06490, Bahçelievler, Ankara, Turkey
Phone: +90 3223272727
Figure 1. Peripheral Blood Smear and Bone Marrow Aspiration
Figure 2. Bone Marrow Aspiration and Biopsy