Reduced-intensity allogeneic stem cell transplantation in children and young adults with ultrahigh-risk pediatric sarcomas

Abstract

Some subsets of pediatric sarcoma patients have very poor survival rates. We sought to determine the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric sarcoma populations with <25% predicted overall survival (OS). Patients with ultrahigh-risk Ewing's sarcoma family of tumors (ESFT), alveolar rhabdomyosarcoma, or desmoplastic small round cell tumors received EPOCH-fludarabine induction, a cyclophosphamide/fludarabine/melphalan preparative regimen, and HLA matched related peripheral blood stem cells. Thirty patients enrolled; 7 did not undergo alloHSCT because of progressive disease with diminishing performance status during induction. All 23 alloHSCT recipients experienced rapid full-donor engraftment, with no peritransplantation mortality. Five of 23 alloHSCT recipients (22%) remain alive (OS of 30% by Kaplan-Meier analysis at 3 years), including 3 of 7 (42%) transplanted without overt disease (median survival 14.5 versus 29.0 months from alloHSCT for patients transplanted with versus without overt disease, respectively). Among the 28 patients who progressed on the study, the median survival from date of progression was 1.9 months for the 7 who did not receive a transplant compared with 11.4 months for the 21 transplanted (P = .0003). We found prolonged survival after posttransplantation progression with several patients exhibiting indolent tumor growth. We also saw several patients with enhanced antitumor effects from posttransplantation chemotherapy (objective response to pretransplantation EPOCH-F was 24% versus 67% to posttransplantation EOCH); however, this was associated with increased toxicity. This largest reported series of alloHSCT in sarcomas demonstrates that alloHSCT is safe in this population, and that patients undergoing alloHSCT without overt disease show higher survival rates than reported using standard therapies. Enhanced chemo- and radiosensitivity of tumors and normal tissues was observed posttransplantation.

Conflict of interest statement

Disclosures:

The authors of this manuscript have no financial conflicts of interest to disclose.

The authors are employees of the United States Government, and, as such, this work was done in that capacity. The views expressed do not necessarily represent the views of the National Institutes of Health or the United States Government.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERES

The authors have no relevant conflicts to disclose.

Published by Elsevier Inc.

Figures

Figure 1

Immune Recovery. Median cell count recovery of lymphocyte subsets over time. The “Post” time point reflects cell counts following EPOCH-F cycles. Day 0 reflects cell counts on the day of transplant following the preparative regimen, where effective immune depletion was achieved and reflected by mean CD 4 counts of 0. Patients achieved normal levels by 6 months post transplant and sustained these levels over time (norms are represented by dashed lines).

Figure 2

Clinical Outcomes. Overall survival (OS) Kaplan-Meier survival curves are shown for: (A) all patients enrolled on study; showing patients who were transplant and non-transplanted. (B) Comparison of survival from transplant for NED patients vs. those with overt disease at transplant (p=0.074). (C) Survival post-alloHSCT based upon high-risk clinical characteristics (p=NS). (D) Survival post-alloHSCT based upon histology (p=NS).

Figure 3

Prolonged Survival Despite Early Post-transplant Relapse. Survival (mos) for individual patients are shown by horizontal bars. Patients not receiving alloHSCT (red) have short survivals following relapse, whereas transplanted patients (blue, green) experienced prolonged survival following relapse. Patients in green represent surviving patients (only #21 has not relapsed). Patient #17* died of bronchiolitis obliterans following post-transplant lung irradiation.

Figure 4

Indolent Growth of Recurrent Ewing’s Sarcoma following alloHSCT. Patient #15 showed persistent disease at the first post-transplant restaging (Day 42). No systemic therapy was administered due to patient choice and he showed minimal progression of disease over an 8-month period.