Trial Information

High Dose Thiotepa and Melphalan With Autologous Hematopoietic Stem Cell Transplant in Children and Adolescents With Solid Tumors

Despite progress in the treatment of children and adolescents suffering from solid tumors
and tumors of the CNS, patients with metastatic disease (or with disease with other high
risk features) continue to suffer from relapse when treated with standard chemotherapy
protocols. In these patients, high-dose chemotherapy (HDC) followed by autologous stem cell
transplantation (ASCT) has been proposed as consolidation therapy in this high-risk
population.

The paradigm for successfully utilization of autologous stem cell transplantation is
childhood neuroblastoma. A large, well performed, randomized study in children with high
risk neuroblastoma showed that application of autologous stem cell transplant can lead to
improved disease free and overall survival, effects that were further augmented by the
administration of biological agents with specific activity against this tumor. Smaller
non-controlled studies and case series have shown that ASCT is feasible in children with
solid tumors or with tumors of the central nervous system. Despite the many reports in the
literature, there is little agreement among investigators as to the ideal combination of
chemotherapeutic agents that should be included in the high dose chemotherapy regimen
administered prior to ASCT for these patients. The choice of agents in these protocols is
dictated by the use of drugs whose dose limiting toxicity is hematopoietic, a concern that
is obviated by the subsequent infusion of autologous stem cells. As such, the majority of
HDC protocols exploit the steep dose response curve of alkylating agents, where
administration of high doses had usually been limited by fear of inducing permanent
myeloablation.

A major limitation of many HDC protocols is that many of the alkylating agents that are used
have already been utilized in front line protocols. A further problem in the design of HDC
protocols that is unique to patients suffering from CNS tumors, is that the administered
agents must traverse the blood brain barrier (BBB) in order to reach the site of the tumor.

A major breakthrough in the the application of HDC in children nwith CNS tumors occurred
with the use of Thiotepa, a highly myeloablative bifunctional alkylating agent that
partitions equally across the BBB. Thiotepa is now a mainstay of all HDC protocols for
children with CNS tumors.

Hara et al. pioneered a novel combination of Thiotepa with Melpahlan, also an alkylating
agent, in the treatment of children with a variety of solid tumors. They catalogued the
toxicity of this protocol, and suggested a dose level of each drug in the combination that
led to toxicity levels of grade ≤3. Of note, in the Hara series, some patients also received
high dose Busulfan.

We piloted the Hara protocol in our center on 14 patients and found that the dose levels
suggested in their study were not tolerated well by children in our center. We decided to
modify the Hara protocol by reducing the doses of both Thiotepa and Melphalan to reduce the
incidence of severe gastrointestinal toxicity that our patients experienced. In addition,
after two patients succumbed to fulminant gram positive infections on the original protocol,
we instituted the empiric administration of Vancomycin for primary treatment of febrile
neutropenia in these patients, pending the results of blood cultures. We also decided to
restrict admission to the protocol to patients with minimal amounts of residual disease as
measured by MRI / CT scan or biochemical markers prior to transplant.