Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.

Isik Kaygusuz Atagunduz,Christine Wolschke,Evgeny Klyuchnikov,Nicolaus Kröger,Silke Heidenreich,Maximilian Christopeit,Francis Ayuk,Dietlinde Janson

doi:10.3390/cancers12113098

Isik Kaygusuz Atagunduz, Christine Wolschke + Show 6 more

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https://doi.org/10.3390/cancers12113098

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Abstract

Simple SummaryCurrently, the only curative therapy in myelofibrosis is allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion and second stem cell transplantation are the two main treatment options for myelofibrosis patients who relapse after the first transplantation. The optimal conditioning regimen for the second transplantation in myelofibrosis patients is not well defined. Our study aimed to address this question and showed that treosulfan-based conditioning for second allograft in relapsed myelofibrosis patients resulted in longtime freedom from disease in about 50% of the patients. This data supports the second allogeneic hematopoietic stem cell transplantation with a less toxic treosulfan-based conditioning regimen that is effective in relapsed, donor lymphocyte infusion resistant myelofibrosis patients with long term low transplant-related mortality and relapse rates.Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36–42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II–IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.

Highlights

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder characterized by clonal ineffective hematopoiesis, a reactive reticulin deposition and fibrosis in bone marrow, circulating CD34+ progenitor cells, extramedullary hematopoiesis, and leukemic progression [1]
Prospective and retrospective studies reported an overall survival (OS) rate of 30–60% at 3–5 years for allogeneic hematopoietic stem cell transplantation (AHSCT) with myeloablative conditioning (MAC) regimen in patients with MF and a non-relapse mortality (NRM) rate ranging from 30% to 48% at 1 year, 24% to 43% at 3–5 years [2,3,4,5]
The only retrospective study on MF patients reported that a treosulfan and fludarabine based conditioning for the first AHSCT has a potent myeloablative and antidisease activity [15]

Summary

Introduction

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder characterized by clonal ineffective hematopoiesis, a reactive reticulin deposition and fibrosis in bone marrow, circulating CD34+ progenitor cells, extramedullary hematopoiesis, and leukemic progression [1]. Allogeneic hematopoietic stem cell transplantation (AHSCT) is the only potentially curative treatment option for patients with MF with a cure rate of 30–65% [2,3,4]. Prospective and retrospective studies reported an overall survival (OS) rate of 30–60% at 3–5 years for AHSCT with myeloablative conditioning (MAC) regimen in patients with MF and a non-relapse mortality (NRM) rate ranging from 30% to 48% at 1 year, 24% to 43% at 3–5 years [2,3,4,5]. The use of reduced-intensity conditioning (RIC) has lowered the rate of NRM in comparison with MAC [6,7,8]. Relapse is one of the major causes of treatment failure after AHSCT in MF patients. Clinical relapses can be treated preferentially by donor lymphocyte infusion (DLI) and/or with a second

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