http://www.jco.org/cgi/content/full/23/1/242

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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