Successful unrelated donor stem cell transplantation for advanced myelofibrosis in an adult patient with history of orthotopic liver transplantation

Patriarca et al.1 recently reported a significant improvement in outcome of patients with myelofibrosis (MF) after allogeneic stem cell transplantation (SCT). Some MF patients present to the transplant center with severe complications after a long disease history and their treatment may be very challenging.

In 1987, a 33-year old woman was diagnosed with polycythemia vera (PV) associated with portal and splenic vein thrombosis. A year later she developed acute Budd-Chiari syndrome and required orthotopic liver transplantation. In 2002, 15 years since diagnosis, PV progressed to MF. Molecular genetics revealed heterozygous V617F mutation in the Janus Kinase 2 (JAK 2) gene. In 2006, blood count showed: leukocytes 1.5 × 10/L, hemoglobin 8.1 g/dL, platelets 124 × 10/L and 13% circulating blasts. Blood transfusions were required every eight weeks. According to the Lille Scoring System the patient was at high risk of progression to acute leukemia. Since she had no siblings, we decided to start an unrelated donor search, although very few reports exist on allogeneic SCT in patients after preceding solid organ, respectively liver, transplantation. A compatible donor with a single human leukocyte antigen (HLA) Cw mismatch was identified. Patient and donor were mismatched for blood group and cytomegalovirus serology. In April 2007 allogeneic SCT following treosulfan (30 g/m), fludarabine (150 mg/m) and anti-thymocyte globuline (ATG 30 mg/kg, Fresenius Biotech, Germany) conditioning was performed. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine A and mycophenolate mofetil. Engraftment was achieved rapidly. The first 100 days after SCT were complicated by an asymptomatic CMV reactivation and probable viral encephalitis with lymphocytic pleocytosis in spinal fluid and meningeal MRI enhancement but without positive virology findings. Both episodes were successfully treated with foscarnet. As a further complication, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurred. Acute GVHD or veno-occlusive disease (VOD) did not occur and liver function remained stable. From day 100 onwards, polymerase chain reactions (PCR) of peripheral blood samples were negative for the JAK2 gene mutation consistent with complete molecular remission of MF. Also sustained complete donor chimerism was confirmed by molecular studies. Bone marrow biopsy at day 100 showed a normal hematopoiesis without signs of fibrosis. Imunosuppression was reduced but the patient remained on low-dose cyclosporine A and prednisone as prior to SCT. A biopsy proven chronic scleroderma GvHD of the skin developed eight months after SCT and mycophenolate mofetil was re-started. Sicca symptoms, persistant cachexy and senso-motoric polyneuropathy developed in the following few months. Eighteen months after SCT the blood count showed: leukocytes 4.0/nL, hemoglobin 13.7 g/dL, platelets 112 × 10/L.

In MF allogeneic SCT is the only treatment modality with the potential to provide prolonged disease control or even cure, whereas conventional treatment results are usually disappointing. Recent reports showed hematologic response in up to 100% and complete histopathological remission in 75% of patients with MF who underwent allogeneic SCT.2,3 High rates of molecular remission are achievable in JAK2-positive patients.4 The feasibility of allogeneic bone marrow transplantation (BMT) from a sibling donor following cadaveric liver transplantation has been demonstrated in a pediatric patient with severe aplastic anemia (SAA) following non-A, non-B, non-C (NANBNC) hepatitis.5 Also long-term follow-up after sibling donor BMT for SAA following orthotopic liver transplantation for hepatitis was reported in another pediatric patient.6 Combined cord blood and haplo-identical BMT for SAA after living-related liver transplantation from the same donor was proposed as an option for children with liver failure due to diseases that can be cured by allogeneic SCT.7 A single case of an adult 29-year old patient with SAA, who received myeloablative conditioning for sibling allogeneic BMT four months after orthotopic liver transplantation for NANBNC hepatitis, has been reported.8,9 Severe acute GvHD of the liver was not observed in any of these cases.5–8 It has been suggested by studies in mice and humans that the liver is the most capable of inducing tolerance after solid organ transplantation due to high leukocyte content, particularly due to the antigen-presenting dendritic cells and their progenitors that migrate from the liver into peripheral blood and tissues, modulate immune responsiveness and induce immunological tolerance.10 In this case we could not detect liver-donor derived leukocyte microchimerism for technical reasons after cadaveric liver transplantation. We postulate that microchimerism after solid organ transplantation might facilitate engraftment and prevent GvHD, but further studies are necessary in this field. To our knowledge this is the first report of a successful reduced intensity conditioning allogeneic SCT from an unrelated donor in an adult patient with a history of liver transplantation. This case might encourage physicians to propose allogeneic SCT to patients with hematologic diseases, who had previous liver or other solid organ transplantations.