Pediatr Blood Cancer 2015;62:1645–1649
Radiologic Resolution of Malignant Infantile Osteopetrosis Skeletal Changes Following Hematopoietic Stem Cell Transplantation Amir Pejman Hashemi Taheri, MD,1 Amir Reza Radmard, MD,1 Soheil Kooraki, MD,1 Maryam Behfar, Neda Pak, MD,1 Amir Ali Hamidieh, MD,2* and Ardeshir Ghavamzadeh, MD2 Introduction. Hematopoietic stem cell transplantation (HSCT) is the only known curative treatment of malignant infantile osteopetrosis (MIOP). In this study, short-term serial bone surveys were used to assess radiologic evolution of skeletal changes after HSCT in MIOP. Materials and Methods. Baseline whole-body bone survey was performed in all patients. HSCT was successful in 14 patients (11 with full chimerism, three with mixed chimerism) in whom follow-up bone surveys were carried out at 6 and 12 months after HSCT. Results. Normal corticomedullary differentiation was evident in five (P ¼ 0.06) and 12 (P < 0.005) patients at 6 and 12 months, respectively. Abnormal endobone appearance in long bones, present in 11 participants at baseline exam, disappeared in eight (P ¼ 0.008)
2 MD,
and all (P ¼ 0.001) patients at 6 and 12 months, respectively. In 6month follow-up, rachitic changes significantly disappeared (P < 0.01) in long bones; however, they were evident in ribs of 12 patients (P ¼ 0.50). No patient had rickets in ribs or long bones after 12 months. Conclusion. We observed considerable resolution of MIOP skeletal changes after HSCT in all patients with either full or mixed chimerism. Rachitic changes in long bones, attenuated corticomedullary differentiation, and endobone appearance were the first to resolve. We propose using single long bone plain x-ray to demonstrate short-term skeletal response to HSCT. Pediatr Blood Cancer 2015;62:1645–1649. # 2015 Wiley Periodicals, Inc.
Key words: hematopoietic stem cell transplantation; malignant infantile osteopetrosis; radiologic resolution; skeletal changes
INTRODUCTION Osteopetrosis refers to a spectrum of hereditary skeletal dysplasias which occur as a result of osteoclast dysfunction [1]. Malignant Infantile Osteopetrosis (MIOP) is the most severe form of the disease occurring in one out of every 250,000 births [2]. In this form, osteoclast dysfunction leads to defective bone resorption, marrow space obliteration, severe pancytopenia, and immune dysfunction [3]. Most untreated children with MIOP die within the first decade of life. There is no effective medical therapy that reduces abnormal bone sclerosis and significantly alters the course of the disease. Hematopoietic stem cell transplantation (HSCT) is shown to increase long-term survival and is currently considered as the only curative therapy [4–7]. Successful response to HSCT is seen in 46–79% of patients with MIOP [5,8–9]. Few studies have described the radiographic changes after HSCT in a few cases of MIOP. Considerable evolution in skeleton radiographic appearance is associated with successful HSCT [10–12]. Data regarding changes in skeletal radiology after HSCT are lacking. The aim of the present study was to use serial whole-body bone surveys for short-term assessment of skeletal changes in patients with MIOP after successful HSCT. Moreover, we aimed to compare the skeletal changes in patients bearing mixed chimerism with those of patients having full chimerism.
MATERIALS AND METHODS Study Design and Patient Selection This prospective study was conducted from January 2010 to February 2013. All patients referred to the Hematology/Oncology and Stem Cell Transplantation Research Center (HORCSCT) and presumed to have MIOP were evaluated. Diagnosis of MIOP was made based on the clinical exam, laboratory tests, and typical radiographic skeletal findings and was confirmed by bone biopsy and genetic studies. Baseline whole-body bone survey was carried C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25524 Published online 27 March 2015 in Wiley Online Library (wileyonlinelibrary.com).
out in all patients 1 day before the start of the conditioning regimen. Patients with successful engraftment after HSCT were included in this study. Patients who did not survive beyond 6 months after HSCT were excluded from the study. The design of the study was approved by the institutional review board and local ethics committee of the HORCSCT. Written informed consent was obtained after explaining the study process in detail to the parents or legal guardians of the children.
Transplant Preparation and Procedure Grafts were prepared by deriving stem cells from peripheral blood, bone marrow of a healthy donor or cord blood. Before stem cell infusion, all patients received the same myeloablative conditioning regimen including intravenous (I.V.) busulfan and cyclophosphamide, with or without rabbit anti-thymocyte globulin (Thymoglobulin1, Sanofi-Aventis, Inc., Quebec, Canada). All patients received cyclosporine A with methotrexate as a graftversus-host disease (GvHD) prophylaxis regimen. No patient
Abbreviations: HSCT, hematopoietic stem cell transplantation; HORCSCT, hematology oncology and stem cell transplantation research center; MIOP, malignant infantile osteopetrosis; I.V., intravenous; GvHD, graft-versus-host disease; EFD, erlenmeyer flask-shaped deformity; CBC, complete blood count; PCR, polymerase chain reaction; STR, short tandem repeat; SPSS, the statistical package for the social sciences; EBMT, European Group for Blood and Marrow Transplantation; aGvHD, acute graft-versus-host disease 1
Department of Radiology, Shariati hospital, Tehran University of Medical Sciences, Tehran, Iran; 2Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Conflict of interest: Nothing to declare.
Correspondence to: Amir Ali Hamidieh, Hematology-Oncology and Stem Cell Transplantation Research Center/Tehran University of Medical Sciences, Tehran, Iran. E-mail: [email protected] Received 21 November 2014; Accepted 3 March 2015
1646
Hashemi Taheri et al.
received total body irradiation. All patients were strictly isolated during hospitalization period and received the same supportive care. Assessment and scoring of GvHD were performed according to the standard protocol [13–14]. Mixed chimerism was defined as 5–95% of cells of donor origin in recipients of peripheral blood or bone marrow. Full chimerism was defined as more than 95% of donor stem cells in recipients of peripheral blood or bone marrow.
Radiologic Evaluation and Definitions Skeletal plain x-rays were evaluated by two radiologists and in case of discrepancy the opinion of a third radiologist was taken. Radiologists who assessed the x-rays were blind to the fact that whether the radiographic image was taken before or after treatment. The following 14 discrete radiologic findings of MIOP (13 descriptive signs and one quantitative index) were assessed in each follow-up step: (1) loss of normal corticomedullary differentiation; (2) endobone (bone within bone) appearance in long bones; (3) endobone appearance in flat bones; (4) rachitic changes in ribs; (5) rachitic changes in superior epiphysis of humerus; (6) rachitic changes in inferior epiphysis of humerus, (7) rachitic changes in superior epiphysis of femur; (8) rachitic changes in inferior epiphysis of femur; (9) Erlenmeyer flask-shaped deformity (EFD) in superior metaphysis of humerus (EFD is a consequence of defective bone modeling referring to cortical thinning and loss of normal biconcave meta-diaphyseal curves with flaring at the ends of long bones); (10) EFD in inferior metaphysis of femur; (11) sclerosis of the skull base; (12) harlequin appearance of skull (considerable increase in the density of periorbital bones);
(13) presence of fractures; and (14) the ratio of metaphyseal lucent band diameter to femur length.
Follow-Up and Analysis After discharge, patients were followed up weekly for 1 month, then every 2 weeks up to 100 days, and afterwards on an individual basis, depending on each patient’s condition. To determine hematologic response, complete blood count (CBC), leukocyte differential count, and biochemistry tests were evaluated at each follow-up visit. Chimerism evaluation was carried out on days þ15, þ30 on bone marrow specimens and then on days þ60, þ90, þ180, þ360 on peripheral blood samples by using PCR assay to amplify short tandem repeats (STRs). To determine radiologic response in patients with full or mixed chimerism, follow-up whole-body bone surveys were performed at 6 and 12 months after HSCT. Statistical analysis was performed by the statistical package for the social sciences (SPSS) software (version 11.0) (SPSS, Inc., Chicago, IL). Nonparametric tests (Wilcoxon test, McNemar test) were used to compare findings before and after HSCT. All data are expressed as mean SD.
RESULTS Patients’ Characteristics and Outcome Nineteen pediatric patients with MIOP were initially included in this study. Baseline full body skeletal survey was performed in all patients. Subsequently, five patients died before or shortly after HSCT and, therefore, were excluded from the study. Finally, 14 patients (eight males and six females) were included in this study
TABLE I. Frequency of Data Before and After HSCT Skeletal features
Baseline N (%)
6 months post-HSCT N (%)
12 months post-HSCT N (%)
14 (100%)
9 (64.3%)
2 (14.3%)
P: 0.06 3 (21.4%) P: 0.008 14 (100%) – 12 (85.7%) P: 0.50 0 P:
Radiologic Resolution of Malignant Infantile Osteopetrosis Skeletal Changes Following Hematopoietic Stem Cell Transplantation Amir Pejman Hashemi Taheri, MD,1 Amir Reza Radmard, MD,1 Soheil Kooraki, MD,1 Maryam Behfar, Neda Pak, MD,1 Amir Ali Hamidieh, MD,2* and Ardeshir Ghavamzadeh, MD2 Introduction. Hematopoietic stem cell transplantation (HSCT) is the only known curative treatment of malignant infantile osteopetrosis (MIOP). In this study, short-term serial bone surveys were used to assess radiologic evolution of skeletal changes after HSCT in MIOP. Materials and Methods. Baseline whole-body bone survey was performed in all patients. HSCT was successful in 14 patients (11 with full chimerism, three with mixed chimerism) in whom follow-up bone surveys were carried out at 6 and 12 months after HSCT. Results. Normal corticomedullary differentiation was evident in five (P ¼ 0.06) and 12 (P < 0.005) patients at 6 and 12 months, respectively. Abnormal endobone appearance in long bones, present in 11 participants at baseline exam, disappeared in eight (P ¼ 0.008)
2 MD,
and all (P ¼ 0.001) patients at 6 and 12 months, respectively. In 6month follow-up, rachitic changes significantly disappeared (P < 0.01) in long bones; however, they were evident in ribs of 12 patients (P ¼ 0.50). No patient had rickets in ribs or long bones after 12 months. Conclusion. We observed considerable resolution of MIOP skeletal changes after HSCT in all patients with either full or mixed chimerism. Rachitic changes in long bones, attenuated corticomedullary differentiation, and endobone appearance were the first to resolve. We propose using single long bone plain x-ray to demonstrate short-term skeletal response to HSCT. Pediatr Blood Cancer 2015;62:1645–1649. # 2015 Wiley Periodicals, Inc.
Key words: hematopoietic stem cell transplantation; malignant infantile osteopetrosis; radiologic resolution; skeletal changes
INTRODUCTION Osteopetrosis refers to a spectrum of hereditary skeletal dysplasias which occur as a result of osteoclast dysfunction [1]. Malignant Infantile Osteopetrosis (MIOP) is the most severe form of the disease occurring in one out of every 250,000 births [2]. In this form, osteoclast dysfunction leads to defective bone resorption, marrow space obliteration, severe pancytopenia, and immune dysfunction [3]. Most untreated children with MIOP die within the first decade of life. There is no effective medical therapy that reduces abnormal bone sclerosis and significantly alters the course of the disease. Hematopoietic stem cell transplantation (HSCT) is shown to increase long-term survival and is currently considered as the only curative therapy [4–7]. Successful response to HSCT is seen in 46–79% of patients with MIOP [5,8–9]. Few studies have described the radiographic changes after HSCT in a few cases of MIOP. Considerable evolution in skeleton radiographic appearance is associated with successful HSCT [10–12]. Data regarding changes in skeletal radiology after HSCT are lacking. The aim of the present study was to use serial whole-body bone surveys for short-term assessment of skeletal changes in patients with MIOP after successful HSCT. Moreover, we aimed to compare the skeletal changes in patients bearing mixed chimerism with those of patients having full chimerism.
MATERIALS AND METHODS Study Design and Patient Selection This prospective study was conducted from January 2010 to February 2013. All patients referred to the Hematology/Oncology and Stem Cell Transplantation Research Center (HORCSCT) and presumed to have MIOP were evaluated. Diagnosis of MIOP was made based on the clinical exam, laboratory tests, and typical radiographic skeletal findings and was confirmed by bone biopsy and genetic studies. Baseline whole-body bone survey was carried C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25524 Published online 27 March 2015 in Wiley Online Library (wileyonlinelibrary.com).
out in all patients 1 day before the start of the conditioning regimen. Patients with successful engraftment after HSCT were included in this study. Patients who did not survive beyond 6 months after HSCT were excluded from the study. The design of the study was approved by the institutional review board and local ethics committee of the HORCSCT. Written informed consent was obtained after explaining the study process in detail to the parents or legal guardians of the children.
Transplant Preparation and Procedure Grafts were prepared by deriving stem cells from peripheral blood, bone marrow of a healthy donor or cord blood. Before stem cell infusion, all patients received the same myeloablative conditioning regimen including intravenous (I.V.) busulfan and cyclophosphamide, with or without rabbit anti-thymocyte globulin (Thymoglobulin1, Sanofi-Aventis, Inc., Quebec, Canada). All patients received cyclosporine A with methotrexate as a graftversus-host disease (GvHD) prophylaxis regimen. No patient
Abbreviations: HSCT, hematopoietic stem cell transplantation; HORCSCT, hematology oncology and stem cell transplantation research center; MIOP, malignant infantile osteopetrosis; I.V., intravenous; GvHD, graft-versus-host disease; EFD, erlenmeyer flask-shaped deformity; CBC, complete blood count; PCR, polymerase chain reaction; STR, short tandem repeat; SPSS, the statistical package for the social sciences; EBMT, European Group for Blood and Marrow Transplantation; aGvHD, acute graft-versus-host disease 1
Department of Radiology, Shariati hospital, Tehran University of Medical Sciences, Tehran, Iran; 2Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran Conflict of interest: Nothing to declare.
Correspondence to: Amir Ali Hamidieh, Hematology-Oncology and Stem Cell Transplantation Research Center/Tehran University of Medical Sciences, Tehran, Iran. E-mail: [email protected] Received 21 November 2014; Accepted 3 March 2015
1646
Hashemi Taheri et al.
received total body irradiation. All patients were strictly isolated during hospitalization period and received the same supportive care. Assessment and scoring of GvHD were performed according to the standard protocol [13–14]. Mixed chimerism was defined as 5–95% of cells of donor origin in recipients of peripheral blood or bone marrow. Full chimerism was defined as more than 95% of donor stem cells in recipients of peripheral blood or bone marrow.
Radiologic Evaluation and Definitions Skeletal plain x-rays were evaluated by two radiologists and in case of discrepancy the opinion of a third radiologist was taken. Radiologists who assessed the x-rays were blind to the fact that whether the radiographic image was taken before or after treatment. The following 14 discrete radiologic findings of MIOP (13 descriptive signs and one quantitative index) were assessed in each follow-up step: (1) loss of normal corticomedullary differentiation; (2) endobone (bone within bone) appearance in long bones; (3) endobone appearance in flat bones; (4) rachitic changes in ribs; (5) rachitic changes in superior epiphysis of humerus; (6) rachitic changes in inferior epiphysis of humerus, (7) rachitic changes in superior epiphysis of femur; (8) rachitic changes in inferior epiphysis of femur; (9) Erlenmeyer flask-shaped deformity (EFD) in superior metaphysis of humerus (EFD is a consequence of defective bone modeling referring to cortical thinning and loss of normal biconcave meta-diaphyseal curves with flaring at the ends of long bones); (10) EFD in inferior metaphysis of femur; (11) sclerosis of the skull base; (12) harlequin appearance of skull (considerable increase in the density of periorbital bones);
(13) presence of fractures; and (14) the ratio of metaphyseal lucent band diameter to femur length.
Follow-Up and Analysis After discharge, patients were followed up weekly for 1 month, then every 2 weeks up to 100 days, and afterwards on an individual basis, depending on each patient’s condition. To determine hematologic response, complete blood count (CBC), leukocyte differential count, and biochemistry tests were evaluated at each follow-up visit. Chimerism evaluation was carried out on days þ15, þ30 on bone marrow specimens and then on days þ60, þ90, þ180, þ360 on peripheral blood samples by using PCR assay to amplify short tandem repeats (STRs). To determine radiologic response in patients with full or mixed chimerism, follow-up whole-body bone surveys were performed at 6 and 12 months after HSCT. Statistical analysis was performed by the statistical package for the social sciences (SPSS) software (version 11.0) (SPSS, Inc., Chicago, IL). Nonparametric tests (Wilcoxon test, McNemar test) were used to compare findings before and after HSCT. All data are expressed as mean SD.
RESULTS Patients’ Characteristics and Outcome Nineteen pediatric patients with MIOP were initially included in this study. Baseline full body skeletal survey was performed in all patients. Subsequently, five patients died before or shortly after HSCT and, therefore, were excluded from the study. Finally, 14 patients (eight males and six females) were included in this study
TABLE I. Frequency of Data Before and After HSCT Skeletal features
Baseline N (%)
6 months post-HSCT N (%)
12 months post-HSCT N (%)
14 (100%)
9 (64.3%)
2 (14.3%)
P: 0.06 3 (21.4%) P: 0.008 14 (100%) – 12 (85.7%) P: 0.50 0 P:
