[Show abstract][Hide abstract] ABSTRACT: To determine the diagnostic performance of MR enterography (MRE) for detection and grading of gastrointestinal graft-versus-host disease (GI GvHD) after hematopoietic stem cell transplantation (SCT).
Forty-one patients with known GvHD or suspected GvHD underwent MRE and GI endoscopy with multi-level biopsies. MRE images were reviewed for presence of intestinal wall inflammation. Clinical grading of GI GvHD was performed. Histopathological evaluation (HPE) served as the reference standard.
Overall, MRE demonstrated a per-patient sensitivity of 81.5 % for detection of GI GvHD. The most common findings were intestinal wall thickening (81.5 % of GvHD patients), luminal stenosis (81.5 %), mural contrast enhancement (70.4 %), and ascites (59.3 %). These findings were also observed in other conditions than GvHD. The most frequently involved intestinal segment was the sigmoid colon (63.0 %), followed by the ileum (59.3 %) and the jejeunum (51.9 %). The number of involved segments (r s =0.54, p =0.009) correlated significantly with clinical severity as determined by GvHD grading.
After allogeneic stem cell transplantation, MRE may (1) contribute to detection and localization of GI GvHD, and (2) add information indicating the clinical severity of disease, but findings are unspecific. False negative results may be observed not only in low-grade GI GvHD.
• Magnetic resonance enterography (MRE) allows for detection of GI GvHD • Common findings are wall thickening, stenosis, mural contrast enhancement, and ascites • The extent of GI involvement on MRE correlates with clinical severity of GvHD • Involvement of sigmoid colon and small intestine is common • Findings are unspecific and also observed in other conditions, e.g. infectious enteritis.
[Show abstract][Hide abstract] ABSTRACT: To determine whether umbilical cord blood transplantation (UCBT) is an alternative cure for myelofibrosis (MF), we evaluated 35 UCBT reported to Eurocord. Seven patients had secondary acute myeloid leukemia (AML) at UCBT, median age at UCBT was 54 years. Twenty-four patients received a reduced intensity (RIC) regimen and 17 out of 35 total body irradiation (2-12Gy)-fludarabine-cyclophosphamide (TCF) conditioning. The median follow-up was 24 months. The cumulative incidence of neutrophil recovery at 60 days was 80%. Fifteen patients relapsed after UCBT. The 2-year overall survival and event-free-survival (EFS) were 44% and 30%, respectively. All patients given TCF achieved neutrophil and platelet recovery and the use of TCF was associated with superior EFS in the RIC population (44% vs 0%, p=0.001). Patients with transformation to AML had similar outcomes to patients with less advanced stages. In conclusion, despite graft failure remaining a major concern, the role of UCBT in the management of MF, especially using RIC TCF based regimens, deserves further investigation to improve results.
Biology of Blood and Marrow Transplantation 11/2014; · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs), has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection, and definition of relevant endpoints. Accordingly, a response able to capture the long-term effect of the drug should be selected as the endpoint of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary endpoints, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in MF patients with early disease in randomized studies, and a time to event, like progression-free or event-free survival should be the primary endpoint. Phase III trials aimed at preventing vascular events in PV and ET should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs which facilitates communication between academic investigators, regulatory agencies and drug companies.Leukemia accepted article preview online, 25 August 2014 doi:10.1038/leu.2014.250.
[Show abstract][Hide abstract] ABSTRACT: Acquired chromosomal abnormalities are important prognostic factors in patients with myelodisplastic syndromes treated with supportive care and with disease modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodisplastic syndromes who have received stem cells from Human Leukocyte Antigen-identical siblings. Overall survival at 5-years from transplantation in good-, intermediate-, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (p <0.01). Both the disease status (complete remission versus not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (p <0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia +/- ringed sideroblasts (p=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor risk group, showed within the other three disease-status-at-transplant groups, a hazard ratio of 1.86 (95% C.I. 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from Human Leukocyte Antigen-identical siblings except in patients who are transplanted in Refractory Anemia/Refractory Anemia with Ringed Sideroblasts stage before progression to higher myelodysplastic syndrome stages.
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is the malignancy with the most frequent expression of the highly immunogenic cancer-testis antigens (CTA), and we have performed the first analysis of longitudinal expression, immunological properties, and fine specificity of CTA-specific antibody responses in MM.
Cancer Immunology and Immunotherapy 07/2014; · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with chronic myeloid leukemia relapsing after allogeneic stem cell transplantation may be treated by tyrosine kinase inhibitors and/or by donor lymphocyte infusions. Best strategies and timing of administration of lymphocytes are unclear. We analyzed 155 patients who relapsed after allogeneic stem cell transplantation for chronic myeloid leukemia with disease detectable only by molecular methods and who subsequently received lymphocytes. Transplants were performed in first chronic phase (n=125) or in advanced disease (n=29) from identical siblings (n=84) or unrelated donors (n=71) between 1986 and 2003. They received lymphocytes either during molecular relapse (n=85) or upon progression to more advanced disease between 1993 and 2004. The median interval from relapse to lymphocytes infusion was 210 (0-1673) days. The median follow-up after it was 46 (3-135) months. Overall survival (OS) was 76±4% at 5 years after lymphocyte infusions (89±8% with sibling donors and 63±13% with unrelated donors (p=0.003)). Survival was 69±14% if lymphocytes were given within 6 months of the detection of molecular relapse and 81±10% (p=0.061) if given later; 81±11% if given at molecular relapse versus 71±12% (p=0.26) with more advanced disease. In multivariate analysis survival was worse if the donor was unrelated (HR 2.54 (95% CI 1.15-5.53), p=0.021) and better with lymphocyte infusion beyond 6 months from molecular relapse (HR 0.4 (95%CI 0.19-0.84), p=.0.018). These data confirm the remarkable efficacy of lymphocyte infusion for this disease. There appears to be no advantage of administering it early upon detection of molecular relapse in patients who received allogeneic stem cell transplantation for chronic myeloid leukemia.
[Show abstract][Hide abstract] ABSTRACT: The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdc(scid) and Il2rg(null) alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.
Proceedings of the National Academy of Sciences 05/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment for advanced pancreatic cancer is still very unsatisfactory. Treosulfan is an alkylating agent used for conventional, as well as high-dose chemotherapy regimens, whereby plasma concentrations over 500 μg/ml can be achieved. We investigated the effects of treosulfan on pancreatic cancer cell lines.
Using Panc-1, MIA PaCa-2 and Capan-2 cell lines, we investigated the in vitro cytotoxicity of treosulfan-alone and in combination with gemcitabine, 5-fluorouracil or irradiation.
Treosulfan was potently cytotoxic against all pancreatic cancer cell lines at all concentrations (1-100 μg/ml). Combination of treosulfan and gemcitabine revealed strong synergistic effects independent of the sequence of drug administration. Similarly, synergism was observed with irradiation. Combination of treosulfan and 5-fluorouracil revealed antagonism.
Treosulfan effectively kills pancreatic carcinoma cells in vitro and has synergistic activity in combination with gemcitabine and irradiation. These results warrant further investigation of treosulfan in the treatment of pancreatic cancer.
Anticancer research 04/2014; 34(4):1779-84. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myelofibrosis (MF) is a manifestation of several disorders of hematopoiesis collectively referred to as myeloproliferative neoplasms (MPN). Allogeneic hematopoietic stem cell transplantation (ASCT) is the only therapy with proven curative potential. However, most patients with MF are in the 6(th) or 7(th) decade of life, and only some of these patients have been considered suitable transplant candidates. The development of reduced intensity conditioning regimens with limited toxicity has allowed clinicians to offer ASCT to a growing number of older patients. The availability of Janus Kinase (JAK)1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life of MF patients. These drugs may also impact the decision regarding in particular the timing of ASCT. Future studies need to address the role of JAK1/2 inhibitors in patients who are transplant candidates and determine their role before and, possibly, after transplantation. The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with MF.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2014; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Options to pre-emptively treat impending relapse of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) after allogeneic haematopoietic stem cell transplantation (allo-SCT) continuously increase. In recent years, the spectrum of diagnostic methods and parameters to perform post-transplant monitoring in patients with AML and MDS has grown. Cytomorphology, histomorphology, and chimaerism analysis are the mainstay in any panel of post-transplant monitoring. This may be individually combined with multiparameter flow cytometry (MFC) for the detection of residual cells with a leukaemia phenotype and quantitative real-time polymerase chain reaction (RQ-PCR) to assess gene expression, e.g., of WT1 or the residual mutation load (e.g., in case of an NPM1 mutation). Data evaluating the aforementioned methods alone or in combination are discussed in this review with particular emphasis on data pointing towards their suitability to steer pre-emptive post-transplant interventions such as immunotherapy, chemotherapy or therapy with demethylating agents.
Annals of Hematology 03/2014; · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose reduced allogeneic stem cell transplantation (ASCT) in 57 patients with primary or post ET/PV myelofibrosis with graft function and survival. Patients had IPSS low-risk (n = 1), intermediate-1 (n = 5), intermediate-2 (n = 18), and high-risk (n = 33). Before transplantation 41 patients (72%) had MF- 3 and 16 (28%) MF-2 according WHO. After engraftment on day+30 (± 10 days) 21% had near or complete regression (MF 0-1) of BMF and on day+100 (± 20 days) MF-0-1 was noted in 54%. Patients with MF0-1 on day+100 had a 5-year OS of 96% in contrast to 57% for those with MF-2 or MF-3 (p = 0.04). There was no difference of BMF regression at day+100 between high risk IPSS and low/intermediate risk patients. Complete donor cell chimerism was seen in 81% if BMF was MF-0/MF-1 and in 31% if BMF was MF-2/-3 at day 100. Patient with MF2 or 3 at day 100 were more likely to be transfusion-dependent regarding red blood cell (p=0.014) or platelets (p=0.018). Rapid BMF regression after reduced ASCT resulted in a favorable survival independently of IPSS risk score at transplantation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2014; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Micafungin has been approved for the prophylaxis of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report a single-center experience of three different dose levels regarding efficacy, toxicity, and colonization with Candida ssp. in clinical practice. In total, 150 consecutive adult patients who underwent allo-HSCT received micafungin at a dosage of 50, 100, or 150 mg once daily for primary antifungal prophylaxis. Of those patients receiving more than six d of micafungin prophylaxis, 12/46 (26%), 6/44 (14%), and 9/46 (20%) were switched to empiric antifungal treatment. The frequency of invasive fungal infections (IFIs) according to EORTC criteria did not differ significantly (7/46; 15% vs. 5/44; 11% vs. 5/46; 11%) across the different dosage groups. In the 50-mg group, there was one case of candidemia with C. parapsilosis after 12 d of micafungin prophylaxis. In all three groups, micafungin prophylaxis was well tolerated without any case of toxicity-related treatment discontinuation. Renal function was not significantly altered, while increase of bilirubin was mainly due to concomitant ATG application. The incidence of IFIs is similar irrespective of the micafungin dosage while there was a trend toward more frequent change to empiric antifungal treatment as well as oropharyngeal colonization with candida in the lowest dosage group.