Osteosarcoma Osteosarcoma after allogeneic bone marrow ... - Nature

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Osteosarcoma Osteosarcoma after allogeneic bone marrow transplantation. A report of four cases from the Cooperative Osteosarcoma Study Group (COSS) SS Bielack1, JS Rerin1, R Dickerhoff 2, D Dilloo3, B Kremens4, A von Stackelberg5, J Vormoor1 and H Ju¨rgens1 for the Cooperative German–Austrian–Swiss Osteosarcoma Study Group COSS 1 Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Germany; 2Hematology/Oncology, Johanniter Kinderklinik, St Augustin, Germany; 3Department of Pediatric Hematology and Oncology, University Children’s Hospital Duesseldorf, Germany; 4Department of Pediatric Hematology–Oncology and Endocrinology, University Children’s Hospital Essen, Germany; and 5Department of Pediatric Oncology/Hematology, Charite´ Medical Center, Humboldt-University, Berlin, Germany

Summary: Osteosarcoma, one of the most frequent secondary malignancies after the treatment of young patients with cancer, has only very rarely been observed in association with hematopoietic stem cell transplantation (HSCT). We report four patients who were identified by searching the database of the Cooperative Osteosarcoma Study Group (COSS) for patients whose osteosarcoma arose following HSCT. Transplant indications had been acute lymphoblastic leukemia (3) and sickle cell disease (1), and the stem cell source was bone marrow in all cases (three allogeneic, one syngeneic). All four had received chemotherapy with alkylators as part of their conditioning regimen and/or first line therapy. The conditioning regimen included total body irradiation in three patients. The osteosarcomas arose at the age (adolescence) and sites (around the knee) typical for the disease. All four patients received chemotherapy as part of multimodal osteosarcoma treatment, and all four are currently alive, three in continuous remission at 5 7/12, 2 11/12, and 0 6/12 years and one with relapsed osteosarcoma at 4 1/12 years. One of the osteosarcoma-free survivors suffered a third malignancy, myelodysplastic syndrome. Osteosarcoma should be included among the secondary malignancies that can arise following HSCT. Multimodal therapy according to guidelines for de novo osteosarcoma can lead to long-term survival in selected patients. Bone Marrow Transplantation (2003) 31, 353–359. doi:10.1038/sj.bmt.1703864 Keywords: bone marrow transplantation; neoplasms (second primary); osteosarcoma

Correspondence: Dr S Bielack, Cooperative Osteosarcoma Study Group (COSS), University Children’s Hospital Muenster, Department of Pediatric Hematology and Oncology, Albert-Schweitzer Str. 33, 48129 Muenster, Germany. Received 12 August 2002; accepted 01 October 2002

Hematopoietic stem cell transplants are performed for various malignant and nonmalignant conditions. An everincreasing number of transplant recipients can be expected to achieve long-term survival. These patients carry the risk of developing secondary malignancies. In addition to posttransplant lymphoproliferative disorders, myelodysplastic syndromes, acute leukemias, and lymphomas, these include secondary solid tumors.1 Among the solid malignancies, melanoma and nonmelanoma skin cancer, thyroid carcinoma, cancers of the oral cavity and salivary glands, central nervous system tumors, and, among females, carcinoma of the cervix uteri feature most prominently.2–4 Even though individuals who had cancer in childhood may be at a higher risk of developing bone cancer than any other type of second primary cancer5 and even though the risk of bone and connective tissue tumors may also be slightly increased after HSCT,2 there have been only scanty reports of secondary osteosarcoma after bone marrow transplantation (BMT).2,6–8 To our knowledge, a total of no more than three cases have been published to date. Here, we describe the transplant history, presenting features, treatment course and outcome of four additional patients who developed osteosarcoma following nonautologous BMT.

Patients and methods The database of the Cooperative German–Austrian–Swiss osteosarcoma Study Group COSS (2575 patients with osteosarcoma registered prior to 2002) was searched for patients whose osteosarcoma had developed following (nonautologous) HSCT. COSS is a multi-institutional group that has conducted prospective osteosarcoma studies since 1977.9,10 According to German Pediatric Cancer Registry data, the recruitment of pediatric osteosarcoma patients into the COSS studies has been more or less complete for many years.11 In addition, a considerable number of affected adults were also registered.10 All studies were approved by the local ethics committee and/or the Protocol Review Committees of the German Ministry for Science and Technology or of the German Cancer Society,

Osteosarcoma after bone marrow transplantation SS Bielack et al

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respectively. Informed consent was required from all patients and/or their legal guardians, depending on the patient’s age. For those patients who developed an osteosarcoma after hematopoietic stem cell transplantation (HSCT), the electronic database and patient charts maintained at the COSS data center were searched for information regarding history, disease course and treatment prior to transplant, the transplant procedure, and presentation, treatment and outcome of osteosarcoma. Additional information not available from these records was obtained by direct contact with the referring institutions. Follow-up is current for all eligible patients.

Results Four patients who fulfilled the eligibility criteria for this analysis were identified from the COSS database. Three had been transplanted for acute lymphoblastic leukemia (ALL) and one for sickle cell disease (SCD) HbSS. The stem cell source had been bone marrow in all cases (allogeneic in three, syngeneic in one). The diagnosis of osteosarcoma was established by clinical and X-ray findings and confirmed by open biopsy in all four. All four affected individuals were among 856 osteosarcoma patients registered between 1996 and 2001, while none of 1719 osteosarcomas registered prior to 1996 had developed after BMT. Characteristics of the four patients and their diseases as well as treatment outlines including conditioning regimens and outcome are detailed in Tables 1–3.

Osteosarcoma following ALL In three of the four patients (patients 1–3), the diagnosis leading to transplant had been ALL. Leukemia treatment had been given according to standard pediatric leukemia

Table 1

protocols, ALL-BFM-86,12 COALL-89,13 and, in case of relapse, ALL-BFM-REZ-90,14 and included alkylating agents, epipodophyllotoxins, anthracyclines, antimetabolites, and l-asparaginase in all patients. They were transplanted either because of an early relapse (two) or persistent blasts at the end of induction therapy (one). All patients received total body irradiation (TBI) as part of their conditioning regimens (Table 1). All three have remained in complete remission of their leukemias up to date. Patient 1 (COSS-2301). A 10 10/12-year-old boy presented with common acute lymphoblastic leukemia (cALL) in 1988. His family history was remarkable for a brain tumor in a paternal uncle. A syngeneic BMT from his twin brother was performed in 1991, in second remission after an isolated bone marrow relapse (Table 1). In 1996, 5 3/12 years after BMT, the patient first complained about pain in his right leg. After 1 month, biopsy revealed a high-grade osteosarcoma of the right distal femur, and there were no detectable primary metastases (Table 2). Chemotherapy for osteosarcoma consisted of ifosfamide, cisplatin, carboplatin, etoposide, and 12 courses of high-dose methotrexate. Anthracycline therapy was not possible because of a subclinical cardiomyopathy with abnormal systolic function upon echocardiogram. Surgery was refused and the osteosarcoma was therefore irradiated to a total dose of 57.6 Gy. The patient remained well until 3 3/12 years later (9 7/12 years post-BMT), when he developed bone marrow changes consistent with a diagnosis of myelodysplastic syndrome with 20% myeloid blasts in the bone marrow. Following nonmyeloablative conditioning with busulfan (8 mg/kg) and fludarabine (180 mg/m2), a peripheral blood stem cell transplant was performed utilizing the same syngeneic donor as for the first BMT. When this treatment did not lead to remission, he was reconditioned with

Pretransplant and transplant history

Patient (COSS UPN)

Sex

Family history of malignancy

BMT indication

Chemotherapy

Radiotherapy

Age at BMT

Conditioning regimen

Stem cell source

1 (2301)

Male

Paternal uncle: brain tumor

ALL (common); BM relapse

ALL-BFM-86 ALL-REZBFM90

18 Gy (CNS)

13 8/12 years

BM/syngeneic (brother)

2 (2947)

Male

Negative

ALL (pre B/B-hybrid); BM relapse

ALL-BFM86 (modified)

15 Gy (CNS)

9 6/12 years

ALL-REZBFM90 COALL-89

None

11 0/12 years

None

None

7 2/12 years

TBI 12 Gy (2 2 Gy/d 3d) testis 6 Gy (2 Gy/d 3d) VP16 60 mg/kg TBI 15.75 Gy (2.25 Gy/d 7d) CY 120 mg/kg (60 mg/kg/d 2d) TBI 12 Gy (2 2 Gy/d 3d) VP16 60 mg/kg ALG 3d BU (dose?) CY (dose?)

3 (3056)

Female

Mother: breast cancer

ALL (T-); persistent blasts after induction

4 (2545)

Female

Negative

SCD

BM/MFD (brother)

BM/MUD

BM/MFD (sister)

Abbreviations: BM=bone marrow, CNS=central nervous system, BU=busulfan, CY=cyclophosphamide, VP=etoposide, MFD=matched family donor, MUD=matched unrelated donor. See text for other abbreviations. Bone Marrow Transplantation


355 Table 2

Osteosarcoma presentation

Patient

Latency BMT-osteosarcoma diagnosis

1 (2301)

5 4/12 years

Pain (1 month)

2 (2947)

6 8/12 years

Swelling (1 month)

3 (3056)

2 8/12 years

Pain (3 months)

4 (2545)

6 6/12 years

Pain (2 months)

Symptoms

Histology

Primary site

Primary metastases

Osteosarcoma, high-grade central (mixed) Osteosarcoma, periosteal (grade 3) Osteosarcoma, high-grade central (osteoblastic) Osteosarcoma, high-grade central (NFS)

Distal femur

None

Prox. tibia Distal femur

Bone (solitary, contralateral pubis) None

Prox. tibia

None

Abbreviations: prox.=proximal.

Table 3

Treatment for osteosarcoma and outcome

Patient

Chemotherapy (cumulative doseages)

Local therapy

Response

1 (2301)

Methotrexate (144.000 mg/m2) Ifosfamide (24.000 mg/m2) Cisplatin (480 mg/m2) Carboplatin (1.200 mg/m2) Etoposide (1.200 mg/m2)

Irradiation 57.6 Gy (1.8 Gy/d 32d)

2 (2947)

First line: Methotrexate (24.000 mg/m2) Carboplatin (1.800 mg/m2) Etoposide (1.800 mg/m2) Relapse: Doxorubicin (60 mg/m2) Cisplatin (90 mg/m2) Gemcitabine (continuing) Trofosfamide (continuing)

Primary tumor: Resection, endoprothesis

>50% viable

Primary metastasis: Resection

>50% viable

3 (3056)

Doxorubicin 1.80 mg/m2+ Methotrexate 24.000 mg/m2+ Ifosfamide 12.000 mg/m2+ Cisplatin 240 mg/m2+

Resection, endoprothesis

o50% viable

None

3 2/12 years (0 6/12 years)

NED ALL NED OS

4 (2545)

Doxorubicin (450 mg/m2) Methotrexate (12.000 mg/m2) Ifosfamide (36.000 mg/m2) Cisplatin (720 mg/m2) Carboplatin (600 mg/m2)

Resection, endoprothesis

o10% viable

None

9 5/12 years (2 11/12 years)

NED SCD NED OS

NA

Adverse events

Follow-up since BMT (since OS)

Status

MDS-AML (9 7/12 years post-BMT; 3 3/12 years post-OS), treated by syngeneic BMT from the same donor

10 11/12 years (5 7/12 years)

NED ALL NED OS NED MDS

Inoperable solitary pulmonary metastasis 2 8/1 2 years after osteosarcoma diagnosis, treated with gemcitabine

10 9/12 years

NED ALL AWD OS (stable disease)

(4 1/1 2 years)

Response=percentage of viable tumor in resection specimen. Abbreviations: MTX=methotrexate, CBCDA=carboplatin, VP16=etoposide, DOX=doxorubicin, DDP=cisplatin. NA=not assessable. NED=no evidence of disease, AWD=alive with disease.

melphalan 140 mg/m2 and fludarabin 125 mg/m2 and again received peripheral blood stem cells from the same donor. At the last follow-up, 10 11/12 years after the first transplant for ALL, 5 7/12 years after the diagnosis of osteosarcoma, and 1 year after the second transplant for MDS, the patient was alive in good clinical condition and in remission of all malignancies (Table 3). Patient 2 (COSS-2947). A 7 4/12-year-old boy with a family history negative for cancer was first treated for ALL in 1988. The leukemia reportedly presented with characteristics suggestive of both pre-B and B-cell lineage. In 1991, in second remission after an isolated bone marrow relapse, he received an HLA-identical BMT from his brother (Table 1). His further course was complicated by chronic hepatitis C infection, which was first noticed

in the year following BMT, and by growth failure, for which he received growth hormone treatment for a total of four years. In 1998, 4 11/12 years after BMT, swelling of the right knee was noted. A biopsy performed 5 0/12 years after BMT led to the diagnosis of a periosteal osteosarcoma, grade 3, of the right proximal tibia. A second osteosarcomatous lesion of the left pubic bone was detected upon diagnostic staging (Table 2). Chemotherapy for osteosarcoma consisted of carboplatin, etoposide, and high-dose methotrexate (Table 3), and was complicated by prolonged periods of cytopenia. Both the tibial and the pelvic tumor were resected, but neither had responded well to chemotherapy, with more than 50% viable tumor cells remaining at both sites. A large pulmonary metastasis extending across the diaphragm with a massive hemorrhagic pleural effusion was detected Bone Marrow Transplantation


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2 8/12 years after osteosarcoma diagnosis. Currently, 4 1/12 years after the diagnosis of osteosarcoma and 10 9/12 years after BMT, the patient is alive with stable disease, while being treated with gemcitabine and trofosfamide (Table 3). Patient 3 (COSS-3056). The third patient, an 11 0/12year-old girl, received an HLA-identical graft from an unrelated marrow donor for T-ALL with persistent blasts on day 43 of induction therapy in 1999. Her mother had previously died from breast cancer (Table 1). The girl’s post-transplant course was complicated by CMV encephalitis and GvHD of the skin and gut. Localized high-grade central osteosarcoma of the left distal femur was detected in 2001, 2 8/12 years following BMT, 3 months after pain on the affected region had first been noted (Table 2). Neoadjuvant chemotherapy with doxorubicin, high-dose methotrexate, ifosfamide, and cisplatin was tolerated without severe complications; however, a pathological fracture of the affected leg occurred in the preoperative period. Nevertheless, limbsalvage surgery with reconstruction of the bony defect by a custom endoprothesis was feasible. The osteosarcoma showed an intermediate response to preoperative chemotherapy, grade 4, according to the Salzer-Kuntschik15 scale, corresponding to o50% viable tumor in the resected specimen. At the last follow-up, she was receiving postoperative chemotherapy, 6 months after osteosarcoma diagnosis (Table 3). Tests for germline p53 mutations were negative.

Osteosarcoma following sickle cell disease Patient 4 (COSS 2545). The fourth patient, a 7 2/12 yearold-girl of African descent with a negative family history for cancer, received a BMT from her HLA-identical sister in 1992 for SCD (HbSS) with multiple pulmonary complications, including episodes of the acute chest syndrome and pneumonia. She had never received chemoor radiotherapy prior to the transplant procedure. The conditioning regimen consisted of busulfan and cyclophosphamide (Table 1); GvHD-prophylaxis was with cyclosporin A. The post-transplant course was uneventful until an osteosarcoma of the right proximal tibia was detected in 1998, 6 6/12 years after BMT (Table 2). Treatment of the osteosarcoma consisted of limb-salvage surgery and pre- and postoperative chemotherapy with doxorubicin, high-dose methotrexate, ifosfamide, cisplatin, and carboplatin. The tumor responded well to preoperative chemotherapy (o10% viable histologically). A severe anaphylactoid reaction occurred during the first scheduled methotrexate dose, so that this agent was omitted from further treatment. The postoperative course was complicated by repeated episodes of septicemia, caused by a periprosthetic pseudomonas infection, requiring revision surgery on several occasions and finally necessitating removal of the infected endoprothesis. Nevertheless, the patient was able to receive a full course of chemotherapy and is currently alive without evidence of disease, 2 11/12 years after the diagnosis of osteosarcoma and 8 8/12 years after BMT (Table 3). Bone Marrow Transplantation

Search for similar patients by other multi-institutional osteosarcoma groups The chairmen of the osteosarcoma studies of several large multi-institutional European and American groups (European Osteosarcoma Intergroup, Italian Sarcoma Group, Scandinavian Sarcoma Group, Children’s Oncology Group) were asked whether they were aware of any additional osteosarcomas arising after allogeneic stem cell transplantation in their respective groups. None answered positively.

Discussion The four cases reported here represent the largest group of osteosarcomas arising after BMT reported to date. All four osteosarcomas occurred in adolescents and were situated around the knee, a presentation very typical for osteosarcoma in general.16 Treatment according to guidelines for primary osteosarcoma, modified for previous drug exposure, led to prolonged osteosarcoma-free survival in two of the three patients with sufficient follow-up. There have been very few patients with osteosarcoma after nonautologous BMT published in the literature. Two of them were included in a large series of 19 229 allogeneic transplant patients, which combined the secondary malignancy experience of the International Bone Marrow Transplant Registry (IBMTR) and the Fred Hutchinson Cancer Research Center in Seattle.2,6 Both patients had received TBI as part of their conditioning regimen. Treatment and outcome for one of the two—a girl who received a bone marrow graft for acute myeloid leukemia from her HLA-identical sister at age 9, developed a localized high-grade osteosarcoma of the proximal tibia 2.5 years later, and was successfully treated with surgery and adjuvant chemotherapy-were also reported in detail by the Basle group. Their patient survived without evidence of either malignancy 10 years after BMT.7 The second patient from the combined IBMTR/Seattle series, a boy transplanted for ANLL from an HLA-identical sibling at age 6.5 years, developed the osteosarcoma after a latency of 6.6 years and succumbed to the disease 2.4 years thereafter.6 The third patient whom we were able to identify from the literature was a 44-year-old man who developed an osteosarcoma of the right iliac bone 5 years after an allogeneic BMT from his HLA-identical sister for acute monoblastic leukemia. In addition to TBI, this patient had also received radiation therapy to the legs and pelvic region because of cutaneous leukemic lesions. Despite surgery and chemotherapy with doxorubicin, ifosfamide, thiotepa, and high-dose methotrexate, he later died from metastatic osteosarcoma.8 Various patient- and treatment-related factors may predispose BMT patients to the development of secondary osteosarcomas. Among these, genetic predisposition and cytotoxic chemo- and radiotherapy may be the most important. Three of the four patients reported here and all three other patients reported in the literature6–8 received TBI as part of their conditioning regimen, which has been linked to the development of solid tumors after BMT.2,6 It


is well known that ionizing irradiation can induce the development of malignant bone tumors.17 In fact, radiation-associated osteosarcoma ranks among the most frequent treatment-related secondary cancer in children 18, 19 . Several studies in very large cohorts of pediatric cancer patients have found the risk of osteosarcoma to be closely related to the local dose of radiation.5,20,21 The 12 Gy of TBI are certainly on the lower edge of the dose range held responsible for bone tumor development. However, doses in the range used during TBI have been associated with a more than 10-fold increase in the relative risk of developing bone cancer,5 and it may therefore be assumed that TBI contributed to tumor development in three of our four patients. The studies cited above have also shown that chemotherapy with alkylating agents, which all of the patients reported here received during primary therapy and/or as a part of their conditioning regimen, contributes to the risk of bone tumor formation, the risk being correlated with the cumulative dose given.5,20,21 Patients who have received both alkylators and radiotherapy, as three of our four patients did, seem to carry a particularly high risk.5 Genetic predisposition alone or in combination with cytotoxic therapy can lead to the development of multiple malignancies. It is of note that three of the four patients in our series developed their osteosarcoma following transplants for ALL. An association between osteosarcoma and acute lymphoblastic leukemia has previously been suggested by Italian investigators, who described two patients in whom ALL developed as a secondary malignancy following treatment with chemotherapy, but not radiotherapy, for osteosarcoma.22 Osteosarcoma following ALL, on the other hand, seems to be very rare. No osteosarcomas were detected in a population-based series of eight second malignant neoplasms in 895 childhood ALL patients,23 none among 43 second neoplasms in 9720 children with ALL treated according to the therapeutic protocols of the Children’s Cancer Study Group,24 and only one of 52 second neoplasms among 5006 ALL patients observed by the BFM group until 199725 (corresponding to patient 1 from this report, Schrappe M, personal communication) was an osteosarcoma. Evidence suggestive of a familial cancer predisposition was present in two of our three ALL patients. Both the breast cancer in the mother of patient 3 and the brain tumor in a paternal uncle of patient 1, as well as the diagnosis of ALL in the affected patients themselves, would fit into the spectrum of malignancies associated with the Li–Fraumeni cancer family syndrome,26,27 which has been linked to germline p53 mutations.28,29 Germline p53 mutations are only infrequently seen in sporadic osteosarcomas, but are much more common in patients with a firstdegree relative also suffering from cancer30 and in osteosarcoma patients with multiple malignancies.31,32 Childhood leukemias can also arise in association with germline p53 mutations. However, recent reports suggest that they are very infrequent manifestations.33 Testing for p53 mutations was performed in one of the two patients with a positive family history for cancer, but none was detected. Unfortunately, data concerning the p53 status of the other patient were not available. However, the family

histories and the association of leukemias and sarcomas are at least suggestive of a genetic component. The development of MDS in one of the patients who survived both ALL and osteosarcoma supports the impression that we are dealing with a population prone to develop multiple cancers. To our knowledge, there have been no previous reports of patients with secondary osteosarcoma after BMT for a benign disease, such as in patient 4 from our series, who had been transplanted for SCD. Osteosarcoma in SCD has been described previously.34 It has been suggested that bone infarcts may predispose to the development of malignant bone tumors in patients with SCD;35 however, there is no evidence of an increased incidence of osteosarcomas in this population36 and no bone infarct was reported in our patient. She is also remarkable because she is the first BMT recipient to develop an osteosarcoma without ever having received TBI or any other form of radiotherapy. Rather, her conditioning regimen consisted of busulfan and cyclophosphamide. It seems reasonable to assume that these alkylating agents contributed to the development of her malignancy. In addition to the factors discussed above, immunosuppressive therapy, immunodeficiency, viral infection, and GvHD may also contribute to tumorigenesis following BMT.1 The question as to what extent any of these factors, in addition to pure chance, played a role in our patients, must remain open for speculation. Osteosarcoma arising as a secondary malignancy has long been associated with a bleak prognosis. We37 and others38 have recently been able to show that treatment according to the principles used for primary osteosarcoma may lead to long-term disease-free survival in a significant subgroup of affected individuals. The results reported here and in one previously published patient,7 while hampered by very small numbers and limited follow-up, indicate that this may also be true for osteosarcoma after BMT. They demonstrate that osteosarcoma-directed chemotherapy, adapted to account for previous exposure especially to anthracyclines, can be administered after BMT, albeit not without sometimes substantial side effects. In summary, osteosarcoma must be included among the solid tumors which can develop following BMT. Chemotherapy with alkylating agents and TBI given to young patients, some of whom may carry a genetic susceptibility for cancer, possibly in conjunction with hitherto undefined direct and indirect influences of BMT upon the immune system, may predispose to this complication. The osteosarcomas then tend to manifest at the age – during the period of pubertal growth – and sites – around the knee – which are also typical for de novo osteosarcoma. In selected patients, long-term survival may be achieved with appropriate therapeutic intervention.

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Note added in proof ‘‘Since acceptance of this manuscript for publication, one additional case of osteosarcoma following allogeneic BMT for ALL has been published (Asai et al, Int J. Clin Oncol 2002; 7:318–321). Patient 1 from our series has suffered a Bone Marrow Transplantation


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relapse of his MDS, and patient 2 has succumbed to progressive osteosarcoma.’’

Acknowledgements The COSS studies are supported by Deutsche Krebshilfe. The authors wish to thank M Kevric, S Flege, and B KempfBielack from the COSS-Data Center for their assistance; A Kretschmann from the ALL-BFM-Relapse Study Center, Berlin, U Rohrberg from the Pediatric University Hospital Aachen, G Fleischhack from the Pediatric University Hospital Bonn, and M Schrappe from the ALL BFM Study Center, Hannover for valuable information concerning the reported patients; J Whelan, S Ferrari, M Bernstein, and S Smeland for searching for osteosarcomas post-BMT among the patients from their multi-institutional osteosarcoma groups, and would like to acknowledge the physicians, nurses, data managers, and support staff of the collaborating centers for their active participation.

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Bone Marrow Transplantation