Journal of Clinical Oncology, Vol 23, No 1 (January 1), 2005: pp. 242-244
© 2005 American Society of Clinical Oncology
DOI: 10.1200/JCO.2005.05.940
http://jco.highwire.org
CORRESPONDENCE
Graft-Versus–Ewing Sarcoma Effect and Long-Term Remission Induced by Haploidentical Stem-Cell Transplantation in a Patient With Relapse of Metastatic Disease
Ewa Koscielniak, Ute Gross-Wieltsch, Joern Treuner, Peter Winkler
Olgahospital, Stuttgart, Germany
Thomas Klingebiel
Children's University Hospital, Frankfurt, Germany
Peter Lang, Peter Bader, Dietrich Niethammer
Children's University Hospital, Tübingen, Germany
Rupert Handgretinger
St Jude Children's Research Hospital, Memphis, TN
To the Editor:
The chance of cure is very low for patients with primary metastatic or relapsed rhabdomyosarcoma or Ewing tumors.1-3 In the German multicenter studies CWS-81, -86, -91, and -96, patients older than 10 years at diagnosis with bone or bone marrow metastases had a 5-year event-free survival of 2%.4 This poor outcome is due mainly to the high relapse rate after initial chemotherapy, and patients in remission after double high-dose chemotherapy (HDC) had a median time to relapse of 5.7 months (range, 3 to 9 months). Unfortunately, there is no single survivor registered after relapse.4 Allogeneic transplantation might provide a possible graft-versus-tumor effect, and regression of metastatic lesions has been documented in patients with solid tumors.5-8 To exert a graft-versus-tumor effect, we have performed allogeneic transplantation using a haploidentical donor in a patient with metastatic Ewing sarcoma who relapsed after double HDC.
A previously healthy 15-year-old girl was diagnosed in April 1998 with a disseminated Ewing sarcoma. Magnetic resonance imaging (MRI) scans showed a 10 x 11-cm tumor originating from the thorax wall, with erosion and destruction of the 11th rib, with penetration into the retropleural thoracic and retrocrural space. It extended caudally to the upper left kidney pole and spleen, and laterally into the foramina intervertebralia between Th7 and Th11. Skeletal imaging showed metastatic lesions in the eighth rib and in vertebrae C7, Th1, Th5, Th6, Th7, and L5. A chemotherapy scan showed four lung nodules. Bone marrow aspirated from the right and left posterior iliac spines showed massive tumor cell infiltration at both sites.
After initial chemotherapy, an almost complete remission was achieved (only residual tumor was seen in the primary site in the 11th rib), and she received consolidation with double HDC and autologous hematopoietic stem-cell rescue. MRI after the second HDC showed residual tumor in the 11th rib, which was locally irradiated. The patient remained well for 8 months when routine imaging showed a large new lytic lesion in the right parietal bone (Fig 1A), with a component occupying the extradural space (Fig 1B). A bone scan revealed many other lesions in the C7, L4, and S1 vertebrae and the right iliac bone. After two 8-day courses of low-dose oral trophosphamide and idarubicin, the soft part of the cranial lesion was slightly reduced in size (Fig 1C), but all other lesions remained unchanged. She was then considered a candidate for experimental allogeneic stem-cell transplantation (SCT) to induce a graft-versus-tumor effect. The patient's mother, mismatched at two human leukocyte antigen loci, was chosen as the donor. The graft consisted of isolated mobilized peripheral CD34+ stem cells.9 After conditioning with busulfan, thiotepa, fludarabine, cyclophosphamide, and anti-CD3 antibody (Muronomab), a total of 19.1 x 106/kg CD34+ cells and 104/kg CD3+ donor cells were infused without any further post-transplantation immunosuppressive therapy. Her post-transplantation course was uncomplicated, with only grade 1 skin graft-versus-host disease (GvHD). Since the patient still had disseminated persisting tumor lesions, we started, at day +73 post-transplantation, an immunoaugmenting therapy with low-dose interleukin-2. After two weeks of therapy with interleukin-2, she developed grade 3 skin and gut GvHD. On day +123, grade 4 GvHD of the gut and chronic skin GvHD developed. MRI 6 weeks after allogeneic SCT showed reduction of the cranial tumor (Fig 1D). Bone scans showed the skull and S1 lesions to be unchanged, lesions in L4 and the iliac bone regressing, and no lesion in C7. Eight months after SCT, MRI and bone scans showed a slowly regressing abnormal contrast enhancement in the cranium (Fig 1E), lesions in S1 and the iliac bone, but no L4 and C7 lesions. The residual lesion in the 11th rib remained unchanged. Eleven months after SCT, MRI scan of the cranium was completely normal (Fig 1F), and the skeletal lesions had almost completely resolved. At a follow-up in July 2003 (3.5 years after SCT), the patient was in good clinical condition with no evidence of active disease. Unfortunately, the patient presented with a local relapse in the vertebrae C7 1 month later. The patient's response and the unusually long progression-free survival after allogeneic transplantation is highly suggestive of a graft-versus–Ewing sarcoma effect and has prompted us to study this treatment approach in patients with metastatic pediatric soft tissue sarcoma in a prospective clinical trial.
Fig 1. Magnetic resonance imaging scans of the scull at relapse after high-dose chemotherapy demonstrate a metastasis at the parietal bone (A, rectangle) with a contrast-enhancing soft tissue component adjacent to the external table (B, arrow). Magnetic resonance imaging after oral chemotherapy shows reduction of size (C). Scans at 6 weeks (D), 8 months (E), and 11 months (F) postallotransplantation show a slowly regressing abnormal contrast enhancement with a final complete regression.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
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