[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).
[Show abstract][Hide abstract] ABSTRACT: Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of JAK1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis, which is characterized, biologically, by the activation of the JAK-STAT pathway and, clinically, by bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of myelofibrosis patients, and it may also have a favorable effect on survival. Treatment response apparently does not depend on the presence of a JAK2 V617F mutation. The predominant toxicities are thrombocytopenia and anemia. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently studied in myelofibrosis or other immuno-inflammatory diseases.
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2014; 201:249-57.
[Show abstract][Hide abstract] ABSTRACT: Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as an immunomodulator. Pomalidomide, as the newest immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide, and the response of pomalidomide in relapsed and refractory (RR) multiple myeloma (MM) patients, including those who are refractory to both lenalidomide and bortezomib, has induced notable enthusiasm. Several studies have evaluated continuous (2 mg/day) or alternate (5 mg/2 day) dose schedules of pomalidomide, as well as 2 versus 4 mg schedules, and pomalidomide alone versus in combination with dexamethasone or other antimyeloma agents. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone, subsequent trials investigating pomalidomide combination therapy have been initiated. Among these trials combinations with alkylating agents (cyclophosphamide, bendamustin), anthracyclins (pegylated liposomal doxorubicin), proteasome inhibitors (bortezomib, carfilzomib), and various others can be found. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV and-for AL amyloidosis and MF-has already proven remarkable activity. Due to its potency, pomalidomide was approved by the US Food and Drug Administration (FDA) for RRMM in 2/2013 and has also been approved by the European Medicines Agency (EMA).
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2014; 201:359-72.
[Show abstract][Hide abstract] ABSTRACT: In the era of high-dose chemotherapy and novel antimyeloma agents, the survival of multiple myeloma (MM) patients has substantially improved. Adverse effects, including infections, may however arise in the era of combination antimyeloma therapies. In general, MM patients have shown a risk of varicella zoster virus (VZV) infection of 1-4 %, increasing with bortezomib treatment or transplants, but whether immunomodulatory drugs also bear a risk of VZV/complicated herpes simplex virus (HSV) (e.g., VZV-encephalitis [VZV-E], disseminated VZV-infection [d-VZV-i], or conus-cauda syndrome [CCS]) has not been elucidated. We here assessed VZV, VZV-E, d-VZV-i, and CCS in 93 lenalidomide-treated MM patients, consecutively seen and treated in our department. Patients' data were analyzed via electronic medical record retrieval within our research data warehouse as described previously. Of the 93 MM patients receiving lenalidomide, 10 showed VZV or other complicated VZV/HSV infections. These VZV patients showed defined risk factors as meticulously assessed, including suppressed lymphocyte subsets, substantial cell-mediated immune defects, and compromised humoral immune response. Due to our findings-and in line with an aciclovir prophylaxis in bortezomib and stem cell transplant protocols-we introduced a routine aciclovir prophylaxis in our lenalidomide protocols in May 2012 to minimize adverse events and to avoid discontinuation of lenalidomide treatment. Since then, we have observed no case of VZV/complicated HSV infection. Based on our data, we encourage other centers to also focus on these observations, assess viral infections, and-in those centers facilitating a research data warehouse-advocate an analogue data review as an appropriate multicenter approach.
Annals of Hematology 12/2013; · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The inhibitors of DNA binding (ID) inhibit basic helix-loop-helix transcription factors and thereby guide cellular differentiation and proliferation. To elucidate the involvement of IDs in hematopoiesis and acute leukemias (AL), we analyzed ID2 and ID3 expression in hematopoiesis and leukemic blasts in bone marrow biopsies (BMB). BMB of healthy stem cell donors (n = 19) and BMB of patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MD; n = 19), de novo AML (n = 20), B-acute lymphoblastic leukemia (B-ALL) (n = 23), T-ALL (n = 19), were immunohistochemically stained for ID2 and ID3 expression. The expression patterns were evaluated and quantified for each hematopoietic lineage and each leukemia subtype. In normal BMB, immature granulopoiesis showed weak ID2 and strong ID3 expression, which was lost during maturation (p < 0.001). Erythropoiesis remained negative for ID2/3 (p < 0.001). ID2/3 expression differed between immature granulopoiesis and leukemic blasts (p < 0.001). Moreover, differential ID2/3 expression was seen between AL subgroups: AML, especially AML-MD, had more ID2- (p < 0.001) and ID3-positive (p < 0.001) blasts than ALL. We show a comprehensive in situ picture of ID2/3 expression in hematopoiesis and AL. Morphologically, ID2/3 proteins seem to be involved in the granulopoietic maturation. Importantly, the distinct ID2/3 expression patterns in AL indicate a specific deregulation of ID2/3 in the various types of AL and may support subtyping of AL.
[Show abstract][Hide abstract] ABSTRACT: Abstract The transcription factor Runx1 is affected by aberrations in approximately 20% of cases of AML and its role in the development of AML is well-documented. However, there are only few reports available about the role of other members of the family of Runx transcription factors in leukemogenesis. Recent studies in mice suggest that Runx2 might play a role during leukemogenesis since it was shown to collaborate with the fusion protein Cbfβ-MYH11. We report here on a case of AML in a patient with cleidocranial dysplasia (CCD), a hereditary disorder which is caused by a germline mutation in the Runx2 gene. This mutation abrogated the binding to the DNA and thus generated a Runx2-haploinsufficient background. While we observed a general transcriptional upregulation of Runx2 expression in human AML samples when compared to healthy bone marrow, we found even higher Runx2 expression levels in the AML blasts from our CCD patient (1.6fold increase when compared to a collection of AML samples). We hypothesize that the upregulation in Runx2 expression levels indicated that the AML cells from our CCD patient actively compensated for their genetically pre-determined Runx2 haploinsufficiency. Based on the insights from this unique case of AML we believe that an upregulated expression of Runx2 during leukemogenesis is not only seen in mice but also occurs in humans.
[Show abstract][Hide abstract] ABSTRACT: Most MM patients develop anemia with progression to symptomatic disease. Usually, this is normocytic/normochromic, with normal or low iron and elevated ferritin levels. Because ferritin levels alone do not correctly reflect iron stores, we performed a comprehensive analysis of iron parameters (iron, ferritin, transferrin, transferrin saturation [TRFS]) to more precisely assess patients' iron metabolism.
We analyzed: (1) the frequency of IO vs. ID in 136 consecutive MM patients; (2) the prognostic effect on progression-free (PFS) and overall survival (OS); and (3) specific risk groups according to patients' iron metabolism.
Most patients had normal iron metabolism or ID: median iron, ferritin, transferrin, and TRFS values were 75 μg/dL, 446 μg/L, 195 mg/dL, and 26%, respectively. Ferritin levels of < 400 μg/L, 400 to 1000 μg/L, and > 1000 μg/L were observed in 46%, 30%, and 24%, and TRFS levels < 20%, 20% to 45%, and > 45% in 32%, 46%, and 22% of patients, respectively. When patients with modified (ID or IO) vs. normal iron metabolism were compared, laboratory parameters (prohormone of brain natriuretic peptide, estimated glomerular filtration rate, c-reactive protein, reflecting cardiac, renal, or infectious impairment), and PFS and OS appeared impaired with modified metabolism, albeit age- and disease-specific differences were insignificant.
Normal iron metabolism and ID is more frequent in MM patients than IO. ID and IO correlate with organ impairment and impaired survival in MM. This knowledge should be incorporated into the design of future studies that will determine the benefit of iron supplementation with ID, and iron chelators with IO in MM.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the incidence of posaconazole serum levels below 700 μg/L, the rate of breakthrough infections during posaconazole prophylaxis, and factors influencing posaconazole exposure in daily clinical practice.
Prospective observational study and review of the literature.
Hematology and oncology department in a tertiary care academic medical center.
A total of 31 patients with hematologic diseases: 27 received posaconazole prophylaxis and 4 received posaconazole therapy.
We analyzed 187 posaconazole serum levels from 31 patients (median of five posaconazole levels per patient; range 1-16). The analyses revealed that 80 of 187 levels (43%) were below 700 μg/L, and 68% of patients were found to have at least one measured level below this threshold. Breakthrough invasive fungal infections categorized as probable or possible infections occurred in 4 of 27 patients (15%) receiving the drug as prophylaxis. A multivariate analysis, accounting for repeated measurements per patient, revealed that age (p=0.02) and mucositis (p=0.04) were associated with significantly reduced posaconazole serum levels. A review of the current literature on posaconazole therapeutic drug monitoring data from real-world studies is presented as an overview table, highlighting the frequency of patients with inadequate posaconazole exposure and heterogeneity of factors influencing posaconazole levels.
Therapeutic drug monitoring of posaconazole is an important tool of therapy optimization because oral posaconazole suspension shows unreliable absorption rates and exposure.
[Show abstract][Hide abstract] ABSTRACT: Spindle poison-based therapy is of only limited benefit in acute myeloid leukemia while lymphoblastic leukemia/lymphoma responds well. In this study, we identified the spindle assembly checkpoint protein BubR1 as being downregulated in the vast majority of acute myeloid leukemia patients whereas lymphoblastic cells showed high expression. Accurate function of the spindle assembly checkpoint is pivotal for mediating mitotic delay in response to spindle poisons. Mitotic delay by the spindle assembly checkpoint is achieved by inhibition of anaphase-promoting complex-dependent proteolysis of cyclin B and securin. We demonstrate a link between the repression of the spindle assembly checkpoint protein BubR1 in acute myeloid leukemia and the limited response to spindle poison. In accordance with its established role as an anaphase-promoting complex-inhibitor, we found repression of BubR1 to be associated with enhanced anaphase-promoting complex activity and cyclin B and securin degradation, which leads to premature sister-chromatid separation and failure to sustain a mitotic arrest. This suggests that BubR1 repression in acute myeloid leukemia renders the spindle assembly checkpoint-mediated inhibition of the anaphase-promoting complex insufficient, which facilitates completion of mitosis in the presence of spindle poison. As both direct and BubR1-mediated restoration of cyclin B expression enhanced response to spindle poison, we propose the downstream axis of the spindle assembly checkpoint as a promising target for tailored therapies for acute myeloid leukemia.
[Show abstract][Hide abstract] ABSTRACT: The outcomes of MM patients vary considerably and depend on a variety of host- and disease-related risks. As yet, a comorbidity risk index in MM patients has neither been standardized nor validated.
We conducted an initial analysis in 127 MM patients and developed the FCI, validating it in an independent cohort of 466 MM patients. The FCI includes patients' Karnofsky Performance Status, renal and lung disease status. We compared the prognostic information of this validated FCI with established comorbidity indices (Hematopoietic Cell Transplantation-Specific Comorbidity Index and Kaplan Feinstein), the International Staging System (ISS), MM therapy, and age.
Our validation confirmed that patients with 0, 1, or 2 to 3 FCI risk factors display significantly different overall survival (OS) of not reached, 86, and 39 months, respectively (P < .0001). Via multivariate analysis including the FCI, ISS, therapy, and age, the FCI retained its independent prognostic significance (P < .0015). The combination of the FCI and ISS allowed definition of 3 distinct subgroups with low-risk (FCI 0 and ISS I-II), intermediate-risk (all remaining), and high-risk (FCI 1-3 and ISS III) with OS probabilities at 5-years of 85%, 74%, and 42%, respectively (P < .0001).
Our validation analysis demonstrated that the FCI remains a reliable comorbidity index, is simpler to generate than other available comorbidity scores, and contributes valuable information to the ISS. Their combination allows the definition of low-, intermediate-, and high-risk patients. These results advocate use of the FCI in future prospective studies and might guide personalized treatment strategies.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Preclinical models, by definition, are an approximation of reality, and their use in developing anticancer drugs is eagerly explored. Positive clinical correlations have been identified with different test systems, in addition to limitations and a need to improve preclinical model systems. Predicting whether a potential new anticancer agent will have a positive therapeutic index in patients remains a challenge. Areas covered: We here review the fundamental requirements and remarkable progress of preclinical in vitro and in vivo assays used to assess the therapeutic potential of experimental anticancer drugs in multiple myeloma (MM). In MM, the interaction with the bone marrow microenvironment (BMM) plays a crucial role in disease progression, including resistance to antimyeloma agents. In vitro and in vivo approaches are, therefore, discussed with respect to their ability to mimic the important characteristics of MM and its BMM. In general, MM models should parallel the biological, genetic, etiological, immunological and therapeutic properties of the human disease. Expert opinion: All models discussed here have their defined strengths, but also limitations with respect to their predictive features. Understanding the preclinical models in a more profound way should lead to optimized clinical trials, thereby expanding the therapeutic arsenal and improving patient outcome further.
Expert opinion on biological therapy 06/2013; · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib- and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.
British Journal of Haematology 02/2013; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m(2) and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients 65 years old who relapsed >12 months after the first allograft (n=20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse.Bone Marrow Transplantation advance online publication, 4 February 2013; doi:10.1038/bmt.2012.267.
Bone marrow transplantation 02/2013; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic cell transplantation (allo-HCT) of older or patients with comorbidities has become possible due to new regimens for reduced-intensity conditioning. The use of fludarabine, carmustine and melphalan as the preparative regimen (FBM) reduces toxicity while providing substantial anti-leukemic activity. Chronic GVHD (cGVHD) of the lung or bronchiolitis obliterans syndrome (BOS) remains a serious non-infectious complication contributing to treatment-related morbidity. We conducted a retrospective analysis of 259 patients (median age: 61.5, range: 24-76 years) transplanted after FBM conditioning to identify and characterize clinical risk factors for developing BOS. The cumulative incidence rate of BOS was 4.2% (95% confidence interval (CI): 2.4-7.6%) at 1 year and 8.5% (95% CI: 5.6-12.9%) at 5 years after allo-HCT with a median follow-up of 36.5 (range: 3-136) months. In multivariate analysis, age <55 years at allo-HCT (who received 25% higher carmustin-dose in preparative regimen), pulmonary complications after allo-HCT and GVHD prophylaxis without in-vivo T-cell depletion (cyclosporine-A/ATG or cyclosporine-A/alemtuzumab) were associated with BOS. We observed no significant differences in clinical variables such as smoking or lung diseases before allo-HCT. In contrast to cGVHD affecting other organs, BOS showed no impact on overall survival. In conclusion, we identified risk factors associated with developing BOS after conditioning with a reduced toxicity protocol.Bone Marrow Transplantation advance online publication, 4 February 2013; doi:10.1038/bmt.2013.3.
Bone marrow transplantation 02/2013; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antimitotic agents are frequently used to treat solid tumors and hematologic malignancies. However, one major limitation of antimitotic approaches is mitotic slippage, which is driven by slow degradation of cyclin B during a mitotic block. The extent to which cyclin B levels decline is proposed to be governed by an equilibrium between cyclin B synthesis and degradation. It was recently shown that the 3' untranslated region (UTR) of the murine cyclin B mRNA contributes to the synthesis of cyclin B during mitosis in murine cells. Using a novel live-cell imaging-based technique allowing us to study synthesis and degradation of cyclin B simultaneously at the single cell level, we tested here the role of the human cyclin B 3'UTR in regulating cyclin B synthesis during mitosis in human cells. We observed that the cyclin B 3'UTR was not sufficient to enhance cyclin B synthesis in human U2Os, HeLa or hTERT RPE-1 cells. A better understanding of how the equilibrium of cyclin B is regulated in mitosis may contribute to the development of improved therapeutic approaches to prevent mitotic slippage in cancer cells treated with antimitotic agents.
PLoS ONE 01/2013; 8(9):e74379. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We systematically analyzed multiple myeloma (MM) cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents.
Using flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null) mice (NSG).
Myeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID). Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses.
Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies.
PLoS ONE 01/2013; 8(11):e79939. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HLA-G 14-base pair (bp) polymorphism and soluble human leukocyte antigen G were previously reported to be implicated in allogeneic hematopoietic cell transplantation (allo-HSCT) outcome. However, soluble HLA-G blood levels and the 14-bp insertion-deletion polymorphism were separately assessed in the context of allo-HSCT. The aim of the present study was to examine the influence of the 14-bp insertion/deletion polymorphism of the HLA-G gene together with the soluble HLA-G plasma levels on allo-HSCT complications. We investigated the possible impact of HLA-G 14-bp polymorphism together with the pretransplantation and posttransplantation concentration of soluble HLA-G in 59 patients undergoing allo-HSCT. No association was found between the HLA-G 14-bp polymorphism, the soluble HLA-G level and acute graft-versus-host disease (GvHD), disease recurrence, or death. In contrast with previous reports the present data suggest a weak or negligible involvement of both 14-bp polymorphism on HLA-G gene and sHLA-G concentration in posttransplantation complications such as acute or chronic GvHD, relapse, or death.
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is a curative approach for several diseases predominantly affecting elderly patients. Overall survival is compromised by treatment-related mortality (TRM), GvHD, and relapse. Pretransplant clinical risk indicators in elderly patients qualifying for HCT are highly desirable. Pro-BNP is known as a predictor of death in patients with an increasing variety of clinical conditions and frequently used as a routine parameter for organ complications in the allogeneic transplant setting without well-established scientific evidence. Our hypothesis was that pre-HCT NT-pro-BNP could aid in identifying elderly patients at risk for early mortality. We retrospectively evaluated NT-pro-BNP values in 177 consecutive patients of ≥60 years HCT (2005-2010). In 29.4 % of cases, NT-pro-BNP values were within our institute's normal range (<125 pg/ml). Analysis of different NT-pro-BNP cutoff points by receiver operating characteristics curve for mortality at day +100 revealed no single cutoff value with satisfying specificity and sensitivity. The individual outcome of patients with extremely high NT-pro-BNP values was not associated with an increase in mortality or cardiovascular morbidity. NT-pro-BNP values of patients succumbing to TRM did not differ significantly from those alive or having died of relapse-median 276 vs. 217 pg/ml. In conclusion, pre-HCT NT-pro-BNP was of no convincing prognostic relevance for day 100 mortality.
Annals of Hematology 07/2012; · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We analyzed the safety and efficacy of rituximab plus bendamustine (R-B) in elderly and frail patients with aggressive B-non-Hodgkin lymphoma (a-B-NHL). Few reports have as yet reported on R-B in a-B-NHL, albeit its value for indolent lymphoma vs. R-CHOP has impressively been shown. We assessed 20 consecutive patients with a-B-NHL receiving R-B as first-line or relapse treatment after (R)-CHOP in our department. Besides patient- and lymphoma-specific characteristics, comorbidity indices were determined. The median patient age was 72 years (51-86), the median Karnofsky performance status was 55 % (40-90 %), and according to the international prognostic index, 15 had high-intermediate or high-risk disease. The comorbidity indices revealed a median Kaplan-Feinstein index of 3 (range 1-3), Charlson comorbidity index of 4 (range 0-9), hematopoietic cell transplantation-specific comorbidity index of 3 (range 0-11), and Freiburg comorbidity index of 2 (range 0-2). Moreover, eight patients had echocardiographic and laboratory signs of cardiac insufficiency, all leading to R-B rather than R-CHOP treatment. The overall response rate was 55 %, with complete response and partial response rates of 20 and 35 %, respectively. In our frail and elderly patient cohort, R-B therapy was well-tolerated. Median progression free survival and overall survival were 8.3 months (95 % confidence interval [CI], 2.8-not reached [n.r.]) and 19.4 months (95 % CI, 4.6-n.r.), respectively. We conclude that R-B is a feasible and safe therapy option in a-B-NHL patients not qualifying for R-CHOP but needs to be further assessed in larger subsequent trials, these currently being under way.
Annals of Hematology 06/2012; 91(10):1579-86. · 2.87 Impact Factor