ABSTRACTmedian age who had been transplanted over the same period, was examined for correlation of the post-transplantation disease course with JAK2 p.V617F allele burden at day 28. The clinical profiles of the patients are shown in Table 1, individual risk profile, MPN subtype and JAK2 p.V617F allele burden prior to SCT are presented in Table 2A/B. Applying the Dynamic International Prognostic Scoring System (DIPSS) for risk stratification, the patients with primary myelofibrosis (n=16) were classified into either the intermediate-2 risk group or the high risk group. The patients were followed for a median of 43.5 months (range, 20.3 -104.4 months). All patients gave written informed consent to participation in the study in accordance with the Declaration of Helsinki, and the study was approved by the local ethics committee and the national health authorities. Within the first cohort the JAK2 p.V617F allele burden of one patient (UPN6) never exceeded 4%. This patient had an abnormal karyotype and atypical spindle-shaped mast cell aggregates were seen following allogeneic SCT. Together with the molecular pathological finding of a KIT p.D816V mutation the disease was identified as systemic mastocytosis associated with a JAK2 p.V617F-positive MPN. The other 13 patients were determined to have classical MPN which in four of them had transformed to secondary acute myeloid leukemia prior to the allogeneic SCT. All patients in the second cohort (n=16) had classical MPN which in seven cases had transformed to secondary AML prior to transplantation. Patients were transplanted due to progression under conventional treatment with at least one of the following features: secondary AML; increased transfusion frequency; pancytopenia or uncontrolled white blood cell counts under therapy.The success of allogeneic SCT was assessed on the basis of clinical data, cytological, histomorphological and laboratory findings. Relapse was indicated by the reappearance of MPN-typical changes in peripheral blood (i.e. progressive cytopenia, leukerythroblastic blood counts) and/or by clinical symptoms (i.e. increase in splenomegaly, constitutional symptoms) together with characteristic changes in the bone marrow such as progressive fiber density in a trephine biopsy or an increase of atypical blasts in the absence of uncontrolled graft-versushost disease, graft rejection or poor bone marrow function and infections. Response or remission of MPN was indicated by constant or decreasing spleen size and blood count parameters as well as a return to normal histomorphology. SamplesFor the initial study of 14 patients a total of 70 peripheral blood samples were immediately frozen at -80°C. At the same time as the blood sampling, 76 bone marrow biopsies were obtained from the posterior iliac crest. The biopsies were fixed in phosphate-buffered formaldehyde solution (4%) for 12 h. Further processing included decalcification in 10% buffered ethylene-diamine tetra-acetic acid (EDTA), pH 7.2 for 6 h and embedding in paraffin. Early sampling was carried ...
Hepatic complications contribute to morbidity and mortality after allogeneic hemopoietic SCT. Liver Doppler ultrasound and elastography represent promising methods for pretransplant risk assessment and early detection of complications. Ultrasound (liver and spleen size, liver perfusion) and elastography (transient elastography (TE); right liver lobe acoustic radiation force impulse imaging (r-ARFI); left liver lobe ARFI (l-ARFI)) were prospectively evaluated in patients with indications for allo-SCT. Measurements were performed before and repeatedly after SCT. Results were compared with the incidence of life-threatening complications and death during the first 150 days after SCT. Of 59 included patients, 16 suffered from major complications and 9 of them died within the follow-up period. At baseline, liver and spleen size, liver perfusion, TE and r-ARFI did not differ significantly between patients with and without severe complications. In contrast, l-ARFI was significantly elevated in patients who later developed severe complications (1.58 ± 0.30 m/s vs 1.37 ± 0.27 m/s, P = 0.030). After SCT, l-ARFI values remained elevated and TE showed increasing liver stiffness in patients with complications. The value of conventional liver ultrasound for prediction of severe SCT complications is limited. Increased values for TE and l-ARFI are associated with severe SCT complications and demand further evaluation.
Despite reaching initial CR, most elderly AML patients relapse within 2 years of diagnosis and die within 3 years. Following favourable feasibility and phase II studies, we have investigated the role of allogeneic HCT after low dose TBI as consolidation therapy in these patients. Patients were included within the OSHO and HOVON/SAKK protocols and, upon attaining CR1, were treated after the induction and first consolidation in the OSHO protocol and after the second induction cycle in the HOVON/SAKK protocol. Patients received allogeneic, related HCT whenever a family donor was available. Dedicated HOVON/SAKK and OSHO centers used unrelated HCT in patients lacking a family donor. Between May 7, 2002 and August 15, 2005 a total of 83 patients with a median age of 62 (range 40–74) years received low dose TBI based preparative regimens followed by related (n=54) or unrelated (n=29) HCT. There was no difference in age between patients with related (median 63, range 51–74 years) and unrelated grafts (median 61, range 40–72 years), but secondary AML was more frequent in those receiving unrelated HCT (46%) compared to related HCT (15%). The interval from start of the last chemotherapy to HCT was median 80 (36–206) days and 74 (46–184) days for related and unrelated HCT respectively (p=0.46). Results: Absolute neutrophil counts remained above 500μL−1 in 25% of the patients. A median of 0 (range 0–48) and 0 (range 0–14) units of packed red cells and platelets were required. Six patients (7%) rejected. Acute GvHD grades II–IV was diagnosed in 22% and chronic GvHD at 2 years in 23% of the patients. A total of 18 patients received donor lymphocyte transfusions either for relapse (n=13) or for mixed chimerism/graft rejection. OS at 2 years was 51±7% following related- and 65±0.10% following unrelated-HCT. Similarly, DFS was 39±7% and 54±10% for patients with related and unrelated donors respectively. As in previous protocols, the non-relapse mortality amounted to 22±7% for related and 17±9% for unrelated HCT. The major reason for failure was a RI of 50±9% and 35±10% for related and unrelated HCT respectively. Median follow up reached 22 (range 10–41) months. Age < or >60 years did not influence survival (OS median 54± 7% vs, 59± 10% and DFS 43± 8% vs. 47 ± 10% for ≥ 60 yrs and <60 yrs respectively; p=0.82). Results of patients over ≥ 60 yrs (n=55) were compared to patients ≥ 60 yrs with intermediate and high risk cytogenetics who were treated in the OSHO protocol during the complete study period (n=103), but who received a second consolidation with chemotherapy. The OS at 3 years was 54.0± 7% for the HCT arm and 41.0± 5% for the chemotherapy arm. Conclusions: These results confirm those of a phase II study on referred patients with AML at different stages of disease. Since patients have been entered from diagnosis, comparison with patients receiving chemotherapy as second consolidation, was performed. OS at 3 years was higher in patients receiving HCT than in those receiving chemotherapy.
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