Treatment of Myelofibrosis Using I.V. Treosulfan and Autologous Peripheral Blood Progenitor Cell Transplantation Is Feasible and Results in Hematologic Responses – Long-Term Follow-up and Final Analysis of a One-Armed Clinical Study and of Individual Cases
Authors: Buss Eike C. , Topaly Julian , Kreipe Hans H. , Fruehauf Stefan , Ho Anthony D. 
Published: October 2019

Abstract
Abstract 4514

Introduction:
Myelofibrosis with myeloid metaplasia is a chronic myeloproliferative disorder. The only curative therapy to date is myeloablation followed by allogeneic transplantation. Autologous transplantation after myeloablation with high-dose oral busulfan provides a palliative approach which might lead to a long-term relief of symptoms of the disease and is associated with acceptable morbidity and mortality (Anderson et al., Blood, 2001; 98:586–593). However, busulfan pharmacokinetics after oral administration can vary among patients. On the other hand treosulfan, a bi-functional alkylating drug, can be administered safely i.v. with reliable pharmacokinetics and might be suitable for conditioning of patients with myelofibrosis.

Methods and Results:
In a pilot phase, we treated three patients on an individual basis with an autologous transplantation after myeloablation with treosulfan. Following the encouraging results we initiated a clinical trial. Included were patients with myelofibrosis and a high risk disease according to the 1997 criteria of Cervantes. The study is registered at www.kompetenznetz-leukaemie.de.
As of today we have transplanted 11 patients according to the protocol, 9 in Heidelberg, 1 at the Diakoniekrankenhaus Rotenburg and 1 at the University Hospital Rostock. Age at transplantation ranged from 50 to 69 years. For 10 of 11 patients we have been successful in collecting more than 5×106 CD34+ cells/kg body weight (one patient with 4,9 ×106) after mobilization with G-CSF at 16 μg/kg BW s.c. daily for 4 days. The conditioning regimen was treosulfan for three days (total dose 42 g/m2). Hematologic reconstitution was considerably protracted with a median of 26 days (leucocyte count > 1/nl) compared to autologous transplantation for other indications. One patient died on day 34 post transplantation after cerebral hemorrhage. He suffered from severe transfusion refractory thrombocytopenia already before the transplantation.
The twelve-month follow-up showed symptomatic relief, mostly as freedom from transfusions in 7 of 11 patients. The two survivors are alive after 9 years, one with allogeneic transplantation 2 years and the other with allogeneic transplantation 8 years after autologous transplantation. The median survival of the other 9 patients was 3.5 years after autologous transplantation (0.1 – 7.5 years).

Conclusions:
We conclude that myeloablation with treosulfan and autologous PBPCT for patients with myelofibrosis can provide significant palliation. It is associated with an acceptable morbidity and mortality, taking into account the high-risk nature of the disease. The approach is feasible for high-risk patients that cannot or chose not to undergo allogeneic transplantation.

Disclosures:
Buss: medac GmbH: Research Funding. Off Label Use: Treosulfan, off-label use as an agent for high-dose chemotherapy with subsequent autologous stem cell transplantation. Topaly:medac GmbH: Research Funding. Fruehauf:medac GmbH: Research Funding.