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1.
Transpl Infect Dis ; 22(6): e13415, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32779843

ABSTRACT

BACKGROUND: Community-acquired respiratory viruses (CARV) cause upper and lower respiratory tract infections (URTI/LRTI) and may be life-threatening for recipients of an allogeneic stem cell transplantation (allo-SCT). METHODS: In a prospective study encompassing 4 winter-seasons, we collected throat gargles (TG) at random time points from allo-SCT recipients (patients) and controls and followed them up for at least 3 weeks including repetitive sampling and documentation of symptoms. A Multiplex-PCR system to identify 20 CARV and Mycoplasma pneumoniae was used to detect CARV. RESULTS: One hundred ninety-four patients with 426 TG and 273 controls with 549 TG were included. There were more patients with a positive test result (25% vs 11% in the controls), and the patients had a higher number of positive TG (70 = 16%) compared to controls (32 = 6%) (P < .001). Altogether, 115 viruses were detected. Multiple viruses in one TG (11/48, 34%) and prolonged shedding were only observed in patients (13/48, 27%). Patients had more RSV (18/83, 26%) and adenovirus (15/83, 21%) than controls (both viruses 2/32, 6%). Independent risk factors for the detection of CARV included age >40 years (OR 3.38, 95% CI 1.8-6.4, P < .001) and presence of URTI-symptoms (OR 3.22, 95% CI 1.9-5.5, P < .001). No controls developed a LRTI or died whereas 4/48 (8%) patients developed a LRTI (coronavirus in 2, RSV in 1 and influenza A H1N1 in 1 patient). One patient died of CARV (influenza A H1N1). CONCLUSION: Allo-SCT-recipients have more CARV-infections, exhibit a different epidemiology, have more cases of co-infection or prolonged shedding and have a higher rate of LRTI and mortality.


Subject(s)
Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virology , Stem Cell Transplantation , Virus Diseases/epidemiology , Virus Diseases/virology , Adenoviridae/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Community-Acquired Infections/epidemiology , Community-Acquired Infections/etiology , Community-Acquired Infections/virology , Coronaviridae/isolation & purification , Female , Humans , Immunosuppression Therapy , Influenza A Virus, H1N1 Subtype/isolation & purification , Male , Middle Aged , Mycoplasma pneumoniae/isolation & purification , Prospective Studies , Respiratory Syncytial Viruses/isolation & purification , Respiratory Tract Infections/mortality , Respiratory Tract Infections/physiopathology , Risk Factors , Transplant Recipients , Transplantation, Homologous , Virus Diseases/mortality , Virus Diseases/physiopathology , Virus Shedding , Young Adult
2.
Lancet Haematol ; 7(1): e28-e39, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31606445

ABSTRACT

BACKGROUND: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING: medac GmbH.


Subject(s)
Antineoplastic Agents/therapeutic use , Busulfan/analogs & derivatives , Busulfan/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adult , Aged , Disease-Free Survival , Female , Humans , Male , Middle Aged , Vidarabine/therapeutic use
3.
Case Rep Oncol ; 12(1): 22-28, 2019.
Article in English | MEDLINE | ID: mdl-30792641

ABSTRACT

Infectious complications such as invasive aspergillosis or infection with Stenotrophomonas maltophilia (SM) in immunocompromised patients are associated with a high mortality rate. Our report concerns a 40-year-old male newly diagnosed very severe aplastic anemia (vSAA) who in consequence of a mosquito bite was suffering from skin lesion and consecutive soft tissue phlegmon subsequent to the administration of antithymocyte globulin; a full-thickness autologous meshed skin graft successfully performed to cover skin ulcera after allogeneic stem cell transplantation (SCT). This unusual case illustrates the importance of appropriate diagnosis, anti-infective therapy and close interdisciplinary diagnostic algorithms to minimalize side effects and the selection of resistant strains and to improve patients' outcome.

4.
J Cancer Res Clin Oncol ; 143(12): 2511-2519, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28913558

ABSTRACT

INTRODUCTION: SETBP1 mutations have been established as a diagnostic marker in myeloid malignancies and are associated with inferior survival. Since there is limited data on their clinical impact and stability during disease progression, we sought to investigate the relationship between SETBP1 mutations and disease evolution. METHODS: Bidirectional Sanger sequencing of the SETBP1 gene was performed for 442 unselected patients with World Health Organization (WHO) defined myeloid disorders. Follow-up analysis was performed on samples from 123/442 patients to investigate SETBP1 mutation dynamics. Targeted deep next-generation sequencing for a panel of 30 leukemia-associated genes was established to study SETBP1 cooperating mutations. RESULTS: 10/442 patients (2.3%) had SETBP1 hotspot mutations (MDS/MPN, n = 7, sAML, n = 3), whereas four patients (1%) had SETBP1 non-hotspot mutations (MPN, n = 1; MDS, n = 2; sAML, n = 1). The median overall survival for patients with SETBP1 hotspot mutations, SETBP1 non-hotspot mutations, and SETBP1 wild type was 14 (range 0-31), 50 (range 0-71), and 47 months (range 0-402), respectively. In Kaplan-Meier analysis, SETBP1 hotspot mutations were significantly associated with reduced overall survival compared to SETBP1 non-hotspot mutations and the SETBP1 wild type (p < 0.001). All 10 patients with SETBP1 hotspot mutations died from relapse or disease progression. Three of four patients with SETBP1 non-hotspot mutations are alive with stable disease. Cooperating CSF3R and TET2 mutations were most frequently observed in patients with SETBP1 hotspot mutations. CONCLUSIONS: Patients with SETBP1 hotspot mutations suffered from aggressive disease with rapid evolution and inferior overall survival. Patients with SETBP1 non-hotspot mutations had less aggressive disease and a more favorable prognosis. Diagnostic screens for SETBP1 hotspot mutations may help identifying this dismal patient group and treat them in multicenter clinical studies.


Subject(s)
Carrier Proteins/genetics , Germ-Line Mutation , Leukemia, Myeloid/genetics , Myelodysplastic Syndromes/genetics , Nuclear Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Cohort Studies , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Young Adult
5.
J Cancer Res Clin Oncol ; 142(12): 2603-2610, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27640002

ABSTRACT

INTRODUCTION: Even in the era of proteasome inhibitors and immunomodulatory drugs, the autologous stem cell transplantation after high-dose melphalan continues to represent a standard approach for myeloma patients in first-line therapy. Different mobilization chemotherapies before stem cell apheresis have been published while cyclophosphamide at a dose level of up to 4 g/m2 has been evaluated and is commonly applied. In contrast, lower dose levels of cyclophosphamide (e.g., 1.5 g/m2) did not result in a sufficient collection of stem cells. METHODS: We retrospectively analyzed the impact of "intermediate-dose" (ID-CY, 2.5 g/m2) versus "high-dose" (HD-CY, 4 g/m2) cyclophosphamide in 101 (48 vs. 53) consecutively evaluable myeloma patients (median age 59 years, range 32-72 years) who underwent stem cell mobilization after induction chemotherapy. Successful stem cell harvest was defined as a stem cell yield of at least 5 million CD34 cells per kg bodyweight. Evaluation of toxicity especially considered infectious complications and hematological toxicity in both subgroups. RESULTS: Successful stem cell mobilization was achieved in 40 of 48 (83 %) and 44 of 53 (83 %) patients, respectively. The median time to apheresis (11 vs. 12 days) and the median CD34 content of stem cell harvest (8.3 vs. 7.6 million CD34 cells per kg bodyweight) did not differ significantly between both groups. There was a significant difference of WBC nadir in favor of the cyclophosphamide regimen with 2.5 g/m2 (0.8 vs. 0.3 Gpt/L, p = 0.021), and neutropenic fever was more often observed in patients who received 4 g/m2 cyclophosphamide (34 vs. 15 %, p = 0.078). Importantly, after induction chemotherapy using the VCD regimen (bortezomib, cyclophosphamide, dexamethasone), successful stem cell mobilization was achieved in 26 of 29 (90 %) patients treated with 2.5 g/m2 and 21 of 25 (84 %) patients receiving 4 g/m2 cyclophosphamide, respectively. CONCLUSIONS: ID-CY is safe and highly effective for stem cell mobilization in patients with newly diagnosed myeloma and associated with a reduced toxicity compared to HD-CY.


Subject(s)
Cyclophosphamide/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Multiple Myeloma/therapy , Adult , Aged , Cyclophosphamide/adverse effects , Dose-Response Relationship, Drug , Female , Hematopoietic Stem Cell Mobilization/adverse effects , Hematopoietic Stem Cell Transplantation , Humans , Male , Middle Aged , Retrospective Studies , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Autologous , Treatment Outcome
6.
J Cancer Res Clin Oncol ; 142(7): 1641-50, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27169594

ABSTRACT

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. The polycomb repressive complex 2 (PRC2) has been identified as one of the most frequently mutated epigenetic protein complexes in hematologic cancers. PRC2 acts as an epigenetic repressor through histone H3 lysine 27 trimethylation (H3K27me3), catalyzed by the histone methyltransferase enhancer of zeste homolog 2 protein (EZH2). METHODS: To study the prevalence and clinical impact of PRC2 aberrations in an unselected childhood ALL cohort (n = 152), we performed PRC2 mutational screenings by Sanger sequencing and promoter methylation analyses by quantitative pyrosequencing for the three PRC2 core component genes EZH2, suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED). Targeted deep next-generation sequencing of 30 frequently mutated genes in leukemia was performed to search for cooperating mutations in patients harboring PRC2 aberrations. Finally, the functional consequence of EZH2 promoter hypermethylation on H3K27me3 was studied by Western blot analyses of primary cells. RESULTS: Loss-of-function EZH2 mutations were detected in 2/152 (1.3 %) patients with common-ALL and early T-cell precursor (ETP)-ALL, respectively. In one patient, targeted deep sequencing identified cooperating mutations in ASXL1 and TET2. EZH2 promoter hypermethylation was found in one patient with ETP-ALL which led to reduced H3K27me3. In comparison with healthy children, the EZH2 promoter was significantly higher methylated in T-ALL patients. No mutations or promoter methylation changes were identified for SUZ12 or EED genes, respectively. CONCLUSIONS: Although PRC2 aberrations seem to be rare in childhood ALL, our findings indicate that EZH2 aberrations might contribute to the disease in specific cases. Hereby, EZH2 promoter hypermethylation might have functionally similar consequences as loss-of-function mutations.


Subject(s)
DNA Methylation , Enhancer of Zeste Homolog 2 Protein/genetics , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Promoter Regions, Genetic , Adolescent , Child , Child, Preschool , Epigenesis, Genetic , Female , Humans , Infant , Male
8.
Br J Haematol ; 163(2): 235-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23889083

ABSTRACT

Whole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4·3%), 7 of whom had -7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SETBP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression.


Subject(s)
Biomarkers, Tumor/genetics , Carrier Proteins/genetics , Chromosome Aberrations , Mutation , Myelodysplastic Syndromes/genetics , Nuclear Proteins/genetics , Cell Transformation, Neoplastic/genetics , Chromosome Deletion , Chromosomes, Human, Pair 7 , Disease Progression , Exome , Heterozygote , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myelomonocytic, Chronic/genetics , Male , Recurrence
9.
Nat Genet ; 45(1): 18-24, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23222956

ABSTRACT

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.


Subject(s)
Carrier Proteins/genetics , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Mutation , Nuclear Proteins/genetics , Amino Acid Motifs , Amino Acid Sequence , Amino Acid Substitution , Carrier Proteins/metabolism , DNA-Binding Proteins , Exome , Histone Chaperones/genetics , Histone Chaperones/metabolism , Humans , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/mortality , Molecular Sequence Data , Nuclear Proteins/metabolism , Prognosis , Protein Binding , Protein Interaction Domains and Motifs , Protein Phosphatase 2/metabolism , Sequence Analysis, DNA , Transcription Factors/genetics , Transcription Factors/metabolism
10.
Leuk Lymphoma ; 54(7): 1527-31, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23186533

ABSTRACT

Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies and solid tumors. In BCR-ABL1-negative myeloproliferative neoplasms (MPNs) several different tyrosine kinase fusion events have been described, most commonly involving the genes encoding the platelet-derived growth factor receptor alpha (PDGFRA) or beta (PDGFRB). Since the introduction of small molecule kinase inhibitors, TK fusions have emerged as prime therapeutic targets. Here, we report a recurrent CEP85L-PDGFRB fusion in a patient with eosinophilia and an MPN. The fusion was confirmed by specific amplification of the genomic breakpoints and reverse transcription polymerase chain reaction (PCR). The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L-PDGFRB mRNA or genomic DNA, confirming a long-term molecular remission on imatinib.


Subject(s)
Eosinophilia/complications , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/genetics , Oncogene Proteins, Fusion/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Translocation, Genetic , Amino Acid Sequence , Antineoplastic Agents/therapeutic use , Base Sequence , Benzamides/therapeutic use , Chromosome Breakpoints , Chromosomes, Human, Pair 5 , Chromosomes, Human, Pair 6 , Humans , Imatinib Mesylate , Male , Middle Aged , Myeloproliferative Disorders/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Treatment Outcome
11.
Blood ; 121(3): 468-75, 2013 Jan 17.
Article in English | MEDLINE | ID: mdl-23086750

ABSTRACT

NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Phosphoproteins/genetics , Receptor, Notch1/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , ADP-ribosyl Cyclase 1/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/therapeutic use , Biomarkers, Tumor/genetics , Chlorambucil/therapeutic use , Chromosomes, Human, Pair 12/genetics , Cyclophosphamide/therapeutic use , Education, Medical, Continuing , Female , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Incidence , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Membrane Glycoproteins/genetics , Middle Aged , Prognosis , RNA Splicing Factors , Risk Factors , Trisomy/genetics , Tumor Suppressor Protein p53/genetics , Vidarabine/analogs & derivatives , Vidarabine/therapeutic use
12.
Blood ; 119(5): 1208-13, 2012 Feb 02.
Article in English | MEDLINE | ID: mdl-22053108

ABSTRACT

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.


Subject(s)
Bone Marrow Neoplasms/genetics , Gene Silencing , Myelodysplastic-Myeloproliferative Diseases/genetics , Myeloproliferative Disorders/genetics , Repressor Proteins/genetics , Aged , Aged, 80 and over , Amino Acid Sequence , Cohort Studies , DNA Mutational Analysis , Female , Gene Silencing/physiology , Humans , Male , Middle Aged , Molecular Sequence Data , Polycomb-Group Proteins , Sequence Homology, Amino Acid
13.
J Cancer Res Clin Oncol ; 137(4): 733-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20602238

ABSTRACT

PURPOSE: The prevalence of elderly and comorbid patients (pts) with malignant lymphoma (ML) will steadily increase in future. Elderly patients comprise a heterogeneous population. Comprehensive geriatric assessment (CGA) is an established diagnostic tool in geriatric medicine. However, the prognostic value in patients with ML is unclear. We sought to establish a relationship between results of CGA and survival time in patients with ML. METHODS: Newly diagnosed patients with ML and indication for chemotherapeutical treatment were prospectively recruited in an observational trial. In addition to usual diagnostic work up, a CGA including activities of daily living (ADL), instrumental activities of daily living (IADL) and comorbidities was performed. Association of patients' characteristics and results of CGA with survival were analysed according to Kaplan-Meier method and in a multivariate Cox-regression analysis. RESULTS: About 143 patients were included, median age was 63 years, 63 patients were women. Median follow-up of surviving patients was 62 months. Sixty-six patients died within this time. Advanced age, poor Karnofsky performance status, dependence in ADL and IADL and presence of severe comorbidity were significantly associated with shorter survival time. In a Cox-regression analysis, IADL (HR 2.1; 95% CI 1.1-3.9) and comorbidity (HR 1.9; 95% CI 0.9-3.9) were independent and strongest associated with survival time. CONCLUSION: Results of CGA, such as IADL and comorbidities, are prognostic variables for survival of patients with ML. Results should be validated in homogeneous clinical groups and if confirmed included in diagnostic and therapeutic algorithm.


Subject(s)
Geriatric Assessment , Lymphoma/mortality , Activities of Daily Living , Adolescent , Adult , Aged , Aged, 80 and over , Comorbidity , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged
14.
Ann Hematol ; 84(5): 331-8, 2005 May.
Article in English | MEDLINE | ID: mdl-15726363

ABSTRACT

In patients undergoing allogeneic peripheral blood stem cell (PBSC) transplantation after reduced-intensity conditioning (RIC), graft-versus-host disease (GVHD) represents a major cause of morbidity and mortality. T-cell depletion (TCD) prevents GVHD but carries potential risks of graft failure, opportunistic infections, and disease relapse. We explored ex vivo TCD of stem cell allografts that were administered after RIC treatment. Thirteen high-risk patients with hematological malignancies were treated with a fludarabine/melphalan-based RIC regimen followed by transplantation of immunomagnetically selected CD34(+) PBSC from HLA-identical sibling or matched unrelated donors. Patients were sequentially enrolled in two cohorts: group A (n=6) received antithymocyte globulin (ATG) during conditioning and 10(5) donor T cells/kg at transplantation, while group B (n=7) received 10(6) donor T cells/kg without ATG pretreatment. Primary graft failure occurred in two patients of group A and in one patient of group B. Complete donor chimerism persisting more than 1 year was achieved in two cases per cohort. Acute grade II to IV or chronic extensive GVHD were observed in a total of six patients (group A, 2; group B, 4). Procedure-related deaths were mainly due to severe pneumonia occurring in two patients of group A and in five patients of group B. These results suggest that CD34 selection of reduced-intensity PBSC allografts may cause adverse effects upon specific antimicrobial immunity which can lead to fatal infections, particularly in high-risk patients. In our study, simultaneous add-back of < or =10(6)/kg donor T cells was unable to compensate for this deficiency.


Subject(s)
Antigens, CD34 , Graft vs Host Disease , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , T-Lymphocytes , Vidarabine/analogs & derivatives , Adult , Antilymphocyte Serum/administration & dosage , Antineoplastic Agents, Alkylating/administration & dosage , Cell Fractionation , Cohort Studies , Female , Graft vs Host Disease/microbiology , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/microbiology , Hematologic Neoplasms/mortality , Hematopoietic Stem Cell Transplantation/mortality , Humans , Immunosuppressive Agents/administration & dosage , Male , Melphalan/administration & dosage , Middle Aged , Opportunistic Infections/microbiology , Opportunistic Infections/mortality , Pneumonia, Bacterial/microbiology , Pneumonia, Bacterial/mortality , T-Lymphocytes/transplantation , Transplantation Conditioning , Transplantation, Homologous , Vidarabine/administration & dosage
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