The prognosis of patients with soft tissue sarcomas (STS) such as rhabdomyosarcoma (RMS), Ewing sarcoma (ES), or synovial sarcoma (SS) has improved dramatically in recent decades [1, 2]. However, patients with metastatic disease at the time of diagnosis or with certain histological subtypes (e.g., alveolar RMS (aRMS)) still face a poor prognosis [2,3,4]. Therefore, novel therapeutic strategies are required for these patients.
Haploidentical allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a potentially curative therapy for pediatric patients with refractory or relapsed solid malignancies due to its presumable graft-versus-tumor (GvT) effect . Indeed, various preliminary clinical studies indicated a potential GvT effect in patients with metastatic and relapsed ES , neuroblastoma [5, 7], and hepatoblastoma , accompanied by moderate treatment-related toxicity. Furthermore, rapid platelet and particularly rapid leukocyte recovery following haploidentical allogeneic HSCT suggest potent antitumor responses provided by the newly established donor-derived immune system . However, retrospective analyses in pediatric STS patients found no benefit from non-haploidentical allogeneic HSCT in high-risk STS [9, 10].
Therefore, based on the promising preliminary data and limited treatment options of the case studies with haploidentical allogeneic HSCT, patients with refractory or relapsed STS in line with this prospective single-center trial (EudraCT number 2006-000393-76) were offered haploidentical allogeneic HSCT from a family donor. Safety and outcomes were analyzed.
Patients (children and young adults) with the above-mentioned diseases who received their first allogeneic HSCT in our center between January 1, 2005 and January 1, 2015 were included in this study. CD3/CD19-depleted grafts were used for the transplantation of all patients.
Written informed consent was provided by the patient or/and their legal representative before starting the respective conditioning regimen. The study was registered at EudraCT (2006-000393-76) and approved by the local ethics committee (no. 87/06) and the German regulatory authorities (Paul-Ehrlich-Institut, PEI).
A reduced-intensity conditioning regimen with T-cell depletion in the graft and the host, including fludarabine (5 × 30 mg/m2), thiotepa (2 × 5 mg/kg), melphalan (2 × 70 mg/m2), and a monoclonal anti-CD3 antibody (Ab) (muromonab-CD3, OKT-3®) was employed until withdrawal of the latter. Since January 2011, anti-thymocyte globulin (ATG) Fresenius (3 × 10 mg/kg) was administered instead of OKT-3® along with the aforementioned chemotherapy regimen.
Since January 2014, the conditioning regimen included a 3-day course of clofarabine (3 × 40 mg/m2), etoposide (3 × 100 mg/m2), and cyclophosphamide (3 × 400 mg/m2), followed by a 5-day course employing a monoclonal anti-CD52 Ab (alemtuzumab, Campath®, 5 × 0.1 mg/kg) with fludarabine, thiotepa, and melphalan as mentioned above.
Event-free survival (EFS) was calculated from the date of transplantation to the date of the event, which for EFS was relapse, death, or secondary malignancy, whichever occurred first, and for survival, the date of event was the date of death from any cause. EFS and survival curves were estimated according to the Kaplan–Meier method and compared according to Mantel–Cox test (log-rank test). Cumulative incidence curves for relapse were estimated adjusting for the competing risk of other events and were compared with the Gray test. The proportional hazard assumption was tested by graphical checks. Tests were two-sided, with a 0.05 significance level. Analyses were carried out using IBM SPSS Statistics version 22 and Graph Pad Prism version 6.
Between January 1, 2005 and January 1, 2015, a total of 25 patients were enrolled in this single-center prospective study conducted in Frankfurt/Main, Germany. Two-thirds of the cases consisted of patients with aRMS (n = 17). Furthermore, 2 patients with eRMS (embryonal RMS), 5 patients with ES, and 1 patient with relapsed SS were enrolled. The median age at diagnosis was 12.4 years (range, 3.4–25.1 years) and the median time from diagnosis to transplantation was 10.9 months (range, 5.4–95.9 months). Most of the patients enrolled in this study had achieved complete remission (CR) prior to HSCT (16 out of 25), whereas the remaining patients had shown at least (very good) partial responses at the time of transplantation.
After long-lasting consultation, it was considered problematic to use unrelated volunteer donors for such an experimental approach not knowing whether patients might benefit from haploidentical allogeneic HSCT. Therefore, only family members (parents and adult siblings) were allowed to be donors for these patients. However, only 11 of 25 cases were grafted from true haploidentical donors, with 5 of 10 human leukocyte antigen (HLA) mismatches, whereas the remaining cases showed fewer mismatches. Taken together, 20 of 25 cases qualified as HLA-mismatched family donors (MMFDs), whereas the remaining 5 patients qualified as matched family donors (MFDs) without or with one HLA mismatch.
In all, 20 of 25 cases received uniform conditioning consisting of fludarabine, thiotepa, mephalan, and muromonab-CD3 (OKT-3®). After OKT-3® was no longer available in January 2011, it was necessary to switch the conditioning regimen to fludarabine, thiotepa, melphalan, and ATG. The last two patients enrolled in this study received a conditioning regimen consisting of clofarabine, etoposide, and cyclophospamide, followed by fludarabine, thiotepa, and melphalan plus alemtuzumab. The median time to discharge from hospital after HSCT was short with 31 days (range, 22–61 days).
In summary, the predicted 3-year EFS estimate was 12% and the 3-year overall survival (OS) was 20% (Fig. 1). The vast majority of events observed in this study were early relapses that appeared within the first 2 years after HSCT (Fig. 2); most of the patients succumbed shortly thereafter. Three of the patients enrolled in this study are still in CR at 5, 7, and 8 years after allogeneic HSCT (one patient with aRMS, one patient with eRMS, and the one patient with SS, respectively).
Importantly, no significant difference in EFS or OS between patients who received MFD- and MMFD-HSCT (data not shown) was observed. Furthermore, radiation therapy prior to HSCT had no impact on EFS, neither in patients who received no or only local irradiation of the primary tumor site (n = 14) nor in patients who received radiation therapy of the primary tumor site and of all metastases present at the time of diagnoses (n = 11; p = 0.29;). Lastly, we addressed the question whether bone marrow involvement of the tumor influenced EFS. Patients without bone marrow involvement (n = 13) seemed to show better EFS than the patients with bone marrow involvement (n = 12). However, this difference was not statistically significant (p = 0.16).
Twelve of the 25 treated patients developed mild signs of acute graft-versus-host-disease (aGvHD; grade I–II) while 4 patients showed signs of severe aGvHD (grade III–IV). These patients received immunosuppressive agents, including steroids and cyclosporine A as well as multiple administrations of mesenchymal stromal cells, whereas one of the patients with severe aGvHD also received extracorporal photopheresis as therapy. This patient developed cytomegalovirus infection in parallel, remained refractory to GvHD treatment, and, ultimately, died due to multi-organ failure, while still being in remission.
The overall observed treatment-related mortality (TRM) rate was 12% (3/25) with a predicted 3-year rate of 17% (Fig. 2). Beside the patient with aGvHD, one patient died of cerebral bleeding and one of respiratory failure (bronchiolitis obliterans organizing pneumonia). The prognosis for pediatric patients with STS has improved substantially in recent years [1, 2]. However, the prognosis for patients with relapsed or refractory disease or certain histological subtypes (e.g., aRMS) remains poor [2,3,4]. Based on promising preliminary reports about allogeneic (i.e., haploidentical) HSCT in solid pediatric malignancies, we conducted the study presented here.
Despite this experimental approach, the EFS and OS rates at 3 years after allogeneic HSCT were 12% and 20%, respectively. The observed OS was comparable to retrospective analyses in patients with RMS and ES who received allogenetic HSCT in a non-haploidentical setting [9, 10]. The outcome in most cases was limited by relapse as the overall observed TRM rate was low (12%). Importantly, donor type did not affect outcome although only 11 out of 25 patients received true haploidentical allogeneic HSCT.
In summary, the results of this study indicate that haploidentical allogeneic HSCT in its current state offers no benefit compared to other forms of allogeneic HSCT in pediatric STS patients [9, 10] and is inferior to established standard therapies. For instance, standard maintenance therapy for stage IV STS such as oral trofosfamide, idarubicine, and etoposide (O-TI/E) shows adequate response rates . Additionally, the more severe side effects of allogeneic HSCT such as aGvHD and chronic GvHD must be taken into account, although the TRM observed in this study was moderate at 12% (3 out of 25 patients). Furthermore, allogeneic HSCT is vastly more complex and expensive than standard maintenance therapies on a chemotherapeutic basis. Therefore, we firmly argue against allogeneic HSCT in its current form outside clinical trials for patients with high-grade STS because the results are, in summary, at best equivalent to less intensive therapies such as oral maintenance therapy. Hence, further efforts need to be taken to improve the prognosis of pediatric patients with grade IV or refractory STS.
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MM, MTM, ER, AJ, JS, AW, SH, CC, MB, ES-M, TK, CR, BK, BS, EK, TK, and PB collected, analyzed and interpreted the data. MM, MTM, ER, and PB wrote the manuscript. ER, AJ, JS, AW, TK, CR, BK, BS, EK, TK, and PB enrolled and cared for the patients.
Conflict of interest
The authors declare that they have no conflict of interest.
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Merker, M., Meister, M.T., Rettinger, E. et al. Haploidentical allogeneic hematopoietic stem cell transplantation in patients with high-risk soft tissue sarcomas: results of a single-center prospective trial. Bone Marrow Transplant 53, 891–894 (2018). https://doi.org/10.1038/s41409-018-0088-6
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