[Show abstract][Hide abstract] ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N=37,542; 37%) or autologous (N=65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p<0·0001; HR 0·90;0·85–0·90 per 10years; p<0·001) and autologous HSCT (HR 0·91;0·87–0·96 per 10 patients; p<0·001; HR 0·93;0·87–0·99 per 10years; p=0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2=18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.
[Show abstract][Hide abstract] ABSTRACT: Infections due to vancomycin-resistant enterococci (VRE) are of significant importance in high-risk populations, and daptomycin is a bactericidal antibiotic to treat multidrug-resistant VRE in these patients. The emergence of daptomycin non-susceptibility invasive VRE during daptomycin therapy is a major clinical issue. Here the hypothesis was tested that systemic daptomycin therapy also induces the emergence of daptomycin non-susceptible (DNS-) isolates in colonizing VRE populations. 11 vancomycin-resistant Enterococcus faecium strain pairs recovered from rectal swabs were available for analysis. All initial isolates exhibited daptomycin MICs within the wild type MIC distribution of E. faecium (MIC≤4mg/L). In follow-up isolates from five patients a 4-16-fold daptomycin MIC increase was detected. All patients carrying DNS-VRE received daptomycin (14-28 days) at 4mg/kg body weight, while two patients in whom no DNS-VRE emerged were only treated with daptomycin for 1 and 4 days, respectively. Comparative whole genome sequencing identified DNS-VRE-specific single nucleotide polymorphisms (SNP), including mutations in cardiolipin synthase (Cls), and additional SNPs in independent genes potentially relevant for the DNS phenotype. Mutations within cls were also identified in three additional, colonizing DNS-VRE. Of these, at least one strain was transmitted within the hospital. In none of the VRE isolates tested, pre-existing or de novo mutations in the liaFSR operon were detected. This is the first report documenting the emergence of DNS-VRE in colonizing strains during daptomycin treatment, putting the patient at risk for subsequent DNS-VRE infections and priming the spread of DNS-VRE within the hospital environment.
International journal of medical microbiology: IJMM 10/2015; DOI:10.1016/j.ijmm.2015.09.005 · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.223.
Bone marrow transplantation 10/2015; DOI:10.1038/bmt.2015.223 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary or post-ET/PV myelofibrosis is one of the Philadelphia-negative myeloproliferative neoplasms with worst survival. Allogeneic stem cell transplantation (ASCT) can cure a substantial number of patients but is still not universally applicable due to toxicity which leads to therapy-related morbidity and mortality. In the more recent years, outcome of ASCT has improved by less toxic conditioning regimens and optimization of relapse prevention strategies. The introduction of novel therapies such as JAK2 inhibitors may also be helpful in preparation of the transplant by reducing spleen size and constitutional symptoms. To reduce the risk of relapse, molecular monitoring and adoptive immunotherapy with donor lymphocytes have been introduced. Despite lacking prospective randomized trials, it is justified to offer ASCT to eligible patients with PMF whose median survival is expected to be less than 5 years. This includes patients with intermediate-2 and high risk according to IPSS or DIPSS, respectively. The benefit/risk ratio should be considered in each patient taking also transplant- and patient-specific factors into account.
Current Hematologic Malignancy Reports 08/2015; DOI:10.1007/s11899-015-0279-9 · 2.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic graft versus host disease (cGvHD) is the most common cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated the impact of NIH classification on outcome of patients at our center. Primary endpoint was overall survival at 5 years. Two hundred one patients with cGVHD according to NIH were included. Platelets <100,000/μl on day of diagnosis of cGvHD (HR 2.97, 95 % CI 1.7-5.3, p < 0.001), female donor (HR 1.78, 95 % CI 1.0-3.2, p = 0.05), and reduced intensity conditioning (HR 1.95, 95 % CI 1.0-3.8, p = 0.05) impacted overall survival. Non-relapse mortality (NRM) was higher for patients with low vs. high platelets: 26 % (95 % CI 14-40) vs. 6 % (95 % CI 2-10), p < 0.001, and tended to be higher for female vs. male donor: 14 % (95 % CI 7-23) vs. 7 % (95 % CI 3-13), p = 0.08. Relapse tended to be higher for recipients of reduced intensity conditioning (RIC) vs. myeloablative conditioning (MAC): 33 % (95 % CI 23-43) vs. 20 % (95 % CI 10-31), p = 0.06. After excluding patients with myeloma and lymphoma, IgG serum levels at diagnosis of cGvHD of 122 patients were correlated with survival. IgG levels above normal were associated with worse 2-year overall survival (OS), p = 0.04, compared to normal or low IgG levels. Platelet count at diagnosis remains the most valid prognostic factor for survival of patients with cGvHD even in the era of NIH grading. High IgG level at diagnosis of cGVHD represents a potential negative prognostic parameter that deserves further investigation.
Annals of Hematology 07/2015; 94(10). DOI:10.1007/s00277-015-2452-6 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most patients with multiple myeloma (MM) will relapse after an initial response and eventually succumb to their disease. This is due to the persistence of chemotherapy-resistant tumor cells in the patients' bone marrow (BM) and immunotherapeutic approaches could contribute to eradicating these remaining cells. We evaluated SLLP1 as a potential immunotherapeutic target for MM.
We determined SLLP1 expression in myeloma cell lines and 394 BM samples from myeloma patients (n = 177) and BM samples from healthy donors (n = 11). 896 blood samples and 64 BM samples from myeloma patients (n = 263) and blood from healthy donors (n = 112) were analyzed for anti-SLLP1 antibodies. Seropositive patients were evaluated regarding SLLP1-specific T cells.
Most cell lines showed SLLP1 RNA and protein expression while it was absent from normal BM. Of 177 patients 41% evidenced SLLP1 expression at least once during the course of their disease and 44% of newly diagnosed patients were SLLP1-positive. Expression of SLLP1 was associated with adverse cytogenetics and with negative prognostic factors including the patient's age, number of BM-infiltrating plasma cells, serum albumin, β2-microglobulin, creatinine, and hemoglobin. Among patients treated with allogeneic stem cell transplantation those with SLLP1 expression showed a trend towards a reduced overall survival. Spontaneous anti-SLLP humoral immunity was detectable in 9.5% of patients but none of the seropositive patients evidenced SLLP1-specific T cells. However, antigen-specific T cells could readily be induced in vitro after stimulation with SLLP1.
SLLP1 represents a promising target for the immunotherapy of MM, in particular for the adoptive transfer of T cell receptor-transduced T cells.
Journal of Translational Medicine 06/2015; 13(1):197. DOI:10.1186/s12967-015-0562-5 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple Myeloma (MM) is a plasma cell (PC) malignancy, which despite significant therapeutic advances, is still considered incurable. This is due to the persistence of chemotherapy-resistant minimal residual disease in the patients' bone marrow (BM) after an effective induction therapy. Immunotherapies targeting surface molecules expressed on the bulk of tumor cells and the chemotherapy-resistant, myeloma-propagating cells could play a central role in this clinical setting. We recently described surface molecule CD229 as a potential therapeutic target for MM. In our current study we assessed the expression of CD229 on different PC subtypes and on cells with a myeloma-propagating phenotype in a total of 77 patients with PC dyscrasias independently at two different cancer centers. We found that CD229 was strongly and homogeneously overexpressed on the PC of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, MM, and PC leukemia. CD229 was particularly overexpressed on those PC showing an abnormal phenotype such as expression of CD56. Most importantly, CD229 was also highly expressed on those cells in the patients' BM displaying the phenotype of chemotherapy-resistant and myeloma-propagating cells. In conclusion, our combined findings suggest that immunotherapies targeting CD229 will not only be effective for the bulk of tumor cells but will also help to eradicate chemotherapy-resistant cells remaining in the patients' BM after induction treatment. Hopefully, the design of CD229-specific monoclonal antibodies or chimeric antigen receptor-transduced T cells will help to achieve prolonged remissions or even cures in MM patients.
[Show abstract][Hide abstract] ABSTRACT: Persistent complete donor chimerism is an important clinical indicator for remissions of hematological malignancies after HLA-matched allogeneic stem cell transplantation (SCT). However, the mechanisms mediating the persistence of complete donor chimerism are poorly understood. The frequent coincidence of complete donor chimerism with graft-versus-leukemia effects and graft-versus-host disease suggests that immune responses against minor histocompatibility antigens (mHags) are playing an important role in suppressing the host hematopoiesis after allogeneic SCT. Here, we investigated a possible relationship between donor immune responses against the hematopoiesis-restricted mHag HA-1 and the long-term kinetics of host hematopoietic chimerism in a cohort of 10 patients after allogeneic HLA-matched, HA-1 mismatched SCT. Functional HA-1 specific CTLs (HA-1 CTLs) were detectable in 6/10 patients lysing host-type hematopoietic cells in vitro. Presence of HA-1 CTLs in the peripheral blood coincided with low host hematopoiesis levels quantified by highly sensitive mHag specific PCR. Additionally, co-incubation of host type CD34+ cells with HA-1 CTLs isolated after allogeneic SCT prevented progenitor and cobblestone area forming cell growth in vitro and human hematopoietic engraftment in immunodeficient mice. Conversely, absence or loss of HA-1 CTLs mostly coincided with high host hematopoiesis levels and/or relapse. In summary, in this first study, presence of HA-1 CTLs paralleled low host hematopoiesis levels. This coincidence might be supported by the capacity of HA-1 CTLs isolated after allogeneic SCT to specifically eliminate host type hematopoietic stem/progenitor cells. Additional studies involving multiple mismatched mHags in more patients are required to confirm this novel characteristic of mHag CTLs as factor for the persistence of complete donor chimerism and leukemia remission after allogeneic SCT.
PLoS ONE 03/2015; 10(3):e0119595. DOI:10.1371/journal.pone.0119595 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myelofibrosis is a rare clonal hematopoietic stem cell disorder characterized by chronic myeloproliferation, atypical megakaryocytic hyperplasia, and potential leukemic transformation. We report a case of leukemic transformation detected by F-FDG PET/CT. A 56-year-old woman with myelofibrosis and newly diagnosed space-occupying lesion of the chest wall underwent whole-body PET/CT for further evaluation. F-FDG PET demonstrated marked tracer uptake within that lesion. Histopathological evaluation revealed myeloid sarcoma evidencing leukemic transformation. F-FDG PET/CT is a valuable tool-enabling sensitive detection of leukemic transformation in myelofibrosis, particularly in case of extramedullary organ involvement.
Clinical Nuclear Medicine 02/2015; 40(6). DOI:10.1097/RLU.0000000000000728 · 3.93 Impact Factor