[Show abstract][Hide abstract] ABSTRACT: Background Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. Methods We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. Results After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). Conclusions The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275 .).
Full-text · Article · Jan 2016 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25-26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians.
No preview · Article · Jan 2016 · Leukemia & lymphoma
[Show abstract][Hide abstract] ABSTRACT: The only curative therapy for primary myelofibrosis (PMF) is allogeneic stem cell transplantation (ASCT). However, although we know that patients can benefit from ASCT, we do not know the changes of the expression profile of cytokines and matrix modulation factors. In this first systematic analysis, we evaluated the expression profile of 103 factors before and after transplantation in order to identify potential biomarkers. The expression of fibrosis, inflammation and angiogenesis-associated genes were analysed in a total of 42 bone marrow biopsies: PMF patients (n=14) before and after ASCT and, for control purposes, post-ASCT multiple myeloma cases (n=14) and non-neoplastic haematopoiesis (n=10). In post-ASCT PMF cases, decreased expression of tissue inhibitor of metalloproteinases (TIMP) and platelet-derived growth factor alpha (PDGFA) correlated with bone marrow remodelling and haematological remission. Expression of several other matrix factors remained at high levels and now could contribute to post-ASCT remodelling. This is the first systematic analysis of cytokine expression in post-ASCT PMF bone marrow which shows that normalisation of bone marrow microenvironment is paralleled by decreased TIMP and PDGFA expression.
No preview · Article · Dec 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for Myelodysplastic Syndromes (MDS). Little is known about the prognostic impact of mutations e.g. in TP53 specifically after allo-HSCT. We here describe the prognostic impact of mutations in a panel of 19 genes analyzed by amplicon-based-next-generation-sequencing in a uniformly treated patient cohort. Sixty-two patients with a median age of 61 years suffered MDS with 0-20% bone marrow blasts. IPSS was intermediate-1 (15%) and higher (79%). Conditioning uniformly was performed using a sequential approach in which FLAMSA-chemotherapy was followed by Busulfan-based conditioning. Patients mostly were transplanted from an unrelated donor (77%), 36% of patients received a graft from a mismatched donor. Median number of mutations was 2 (, range 0-6). RUNX1, GATA2, TET2, and CEBPA were the genes most frequently found mutated. TP53, a factor previously reported to confer adverse prognostic impact after allogeneic stem cell transplantation, was mutated in samples from eight patients, one of which showed a silent mutation. With an estimated 5-year-overall/ disease-free-survival of 48±7%/ 41±7%, none of the mutations analyzed showed a prognostic impact in this analysis of the largest uniformly treated cohort thus far. This especially holds true for patients with a mutation in TP53. This article is protected by copyright. All rights reserved.
No preview · Article · Dec 2015 · European Journal Of Haematology
[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.
No preview · Article · Oct 2015 · International journal of medical microbiology: IJMM
[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.
Full-text · Article · Oct 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: In contrast to the upfront setting in which the role of high dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a 1(st) remission in patients with multiple myeloma (MM) is well established, the role of high dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN), the American Society of Blood and Marrow Transplantation (ASBMT), and the European Society of Blood and Marrow Transplantation (EBMT) convened a meeting of MM experts to: 1. Summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy; 2. Propose guidelines for the use of salvage HCT in MM; 3. Identify knowledge gaps; 4 Propose a research agenda and 5. Develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: 1. In transplant eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high dose therapy with HCT as part of salvage therapy should be considered standard; 2. High dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; 3. High dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; 4. The role of post salvage HCT maintenance needs to be explored in the context of well designed prospective trials that should include new agents such as monoclonal antibodies, immune-modulating agents and oral proteasome inhibitors; 5. Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post HCT strategies in patients with short (less than 18 months remissions) after primary therapy; 6. Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing to "best non HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform two transplants early in the course of the disease. In regards to allogeneic HCT the expert committee agreed on the following consensus statements: 1. Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high risk features (i.e cytogenetics, extramedullary disease, plasma cell leukemia or high LDH); 2. Allogeneic HCT should be performed in the context of a clinical trial if possible; 3. The role of post allogeneic HCT maintenance therapy needs to be explored in the context of well designed prospective trials; 4. Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
Full-text · Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[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.
No preview · Article · Aug 2015 · Current Hematologic Malignancy Reports
[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.
Full-text · Article · Jul 2015 · Annals of Hematology
[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.
Preview · Article · Jun 2015 · Journal of Translational Medicine
[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.
No preview · Article · May 2015 · Human Vaccines & Immunotherapeutics