bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravenous Voriconazole (IV-VORI) Prevents Invasive Fungal Infections (IFI) in Patients (pts) with Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS).
Authors: Mattiuzzi Gloria N. , Alvarado Gladys , Kantarjian Hagop M. , Verstovsek Srdan , Cabanillas Maria , Faderl Stefan , Lim Joann T. , Giles Francis , Beran Miloslav , O’Brien Susan , Estey Elihu H. 
Published: October 2019

Abstract
Background: IFI is the most frequent cause of mortality in pts with AML and MDS undergoing chemotherapy. None of the antifungal prophylactic regimens used since 1992 at MD Anderson Cancer Center appeared to be significantly superior in the prevention of IFI.
Study Aims: To compare the efficacy and safety of IV-VORI versus IV-ITRA as antifungal prophylaxis in AML and MDS pts receiving chemotherapy
Patients and Methods: Pts older than 18 years old receiving induction or salvage chemotherapy, without documentation of prior IFI were eligible. Pts were randomized on day 1 of chemotherapy to receive IV-VORI 400 mg q12 h x 2 days followed by 300 MG IV twice per day or IV-ITRA 200 mg q12 h x 2 days followed by 200 mg IV once per day. Prophylaxis continue until recovery from neutropenia, developed possible/proven IFI, complete remission, declared resistant or up to 35 days for induction pts and up to 42 days for salvage pts.
Results: 114 pts were evaluable (49 on IV-ITRA, 65 on IV-VORI). Baseline characteristics were similar in both groups. 102 were induction pts and 12 were on first salvage. Median time on prophylaxis was 21 (induction) and 17 days (salvage) for both groups. 45% pts on IV-ITRA and 48% pts on IV-VORI completed prophylaxis without modification (p=ns). Two pts on IV-ITRA developed IFI (1 disseminated C. glabrata and 1 disseminated Fusarium) as oppose to none on the IV-VORI arm (p=0.101). No significant differences were seen in the number of pts that required empiric antifungal therapy due to persistent fever or possible fungal pneumonia (14% on IV-VORI, 18% on IV-ITRA). 15/49 pts on IV-VORI (23%) versus 4/49 (8%) on IV-ITRA discontinued prophylaxis due to side effects (p=0.036). Reversible increase in the liver function tests (9 on IV-VORI, 4 on IV-ITRA) and hallucinations (5 on IV-VORI) were the most frequent adverse events. Response to induction chemotherapy, overall induction mortality and survival were similar in both groups.
Conclusions: 1) IV-VORI appears to be more efficacious than IV-ITRA in preventing IFI in AML and MDS pts receiving chemotherapy. More pts are needed to confirm this finding. 2) IV-VORI tends to be more toxic than IV-ITRA. The usage of high dose IV-VORI may explain the incidence of side effects.
Long Term Follow-Up Shows No Clinical Benefit for CD34+ Selection of Autologous Transplants Following Myeloablative Therapy in Patients with Newly Diagnosed Myeloma : An EBMT Phase III Randomized Study.
Authors: Bourhis Jean-Henri , Bouko Yasmina , Koscielny Serge , Greinix Hildegard , Derigs Gunter , Salles Gilles , Feremans Walter , Bakkus Marleen , Apperley Jane , Samson Diana , Bjorkstrand Bo , Niederwieser Dietger , Gahrton Gosta , Pico Jose-Luis , Goldschmidt Hartmut 
Published: October 2019

Abstract
CD34+ selection of peripheral blood progenitor cells (PBPC) was used in Multiple Myeloma (MM) in an attempt to reduce tumor cell contamination and relapse rate. From May 1995 to November 1999, 127 patients from 17 EBMT centers with newly diagnosed advanced MM were entered into a phase III trial. Responders to 3 cycles of VAD were randomized to receive either CD34+ selected (arm A) or unselected PBPC (arm B) following myeloablative conditioning treatment. PBPC were harvested following mobilization with cyclophosphamide 4g/m² and G-CSF (Filgrastim, AMGEN, Europe). Conditioning regimen in both arms was TBI and high dose melphalan 140 mg/m². CD34+ cell selection was performed in arm A using the CellPro Ceprate-SC device. The analysis concerns the 111 patients who were transplanted (56 arm A and 55 arm B). The median follow-up at the time of the analysis was 65 months. CD34+ selection resulted in a median purity of 87% and a yield of 50%. Molecular analysis showed a median tumor cell depletion of 2.0 log (range 0.3–85.5). The median number of CD34+ cells reinfused/kg was 5.8 x 106 (1.42–50.4) in arm A and 7.4x106 (1.85–99.2) in arm B. The median time to neutrophil engraftment (ANC >0.5x109/l) was 10 days (range 8–14) in arm A and 10 days (range 8–21) in arm B. The median time to platelet engraftment (plts>20 x 109/l) was 11 days (range 5–26) in arm A and 9 days (range 5–42) in arm B (p=0.005). One patient died before platelets engraftment in arm A. Twelve patients experienced at least one episode of serious infection (total episodes =17) before day 100 in arm A compared to 3 patients (total episodes = 6) in arm B (p=0.02). For 3 patients in arm A, these infections were fatal (including the patient who died before time to platelet engraftment). There was no significant difference in CR rate at 1 year as defined by EBMT/IBMTR/ABMTR criteria (27% in arm A and 20% in arm B). The 5 year overall survival (OS) was 51% in arm A and 45% in arm B (p=0.80). The 5 year event free survival was 20% in arm A and 18% in arm B (p=0.45). The increased incidence of severe infections in the CD34+ selected arm in the early post transplant may be due to impaired immune reconstitution. Thus, no long term clinical benefit is obtained by CD34+ selection despite significant tumor cell reduction.
Addition of Bortezomib (Velcade™) to High Dose Melphalan (Vel-Mel) as an Effective Conditioning Regimen with Autologous Stem Cell Support in Multiple Myeloma (MM).
Authors: Hollmig Klaus , Stover Julie , Talamo Giampalamo , Zangari Maurizio , Thertulien Raymond , van Rhee Frits , Fassas Athanasios , Anaissie Elias , Tricot Guido , Barlogie Bart 
Published: October 2019

Abstract
Velcade has shown promising activity alone and, more recently, in combination with other anti-myeloma agents (dexamethasone, thalidomide, doxil, standard dose melphalan) for relapsed or refractory multiple myeloma. We have now explored the efficacy and safety of Velcade™ 1.0 or 1.3mg/m2 administered on days -4 and -1 prior to Melphalan, which was given in two fractionated doses for a total of 100–250 mg/m2 on days -4 and -1 or as single dosing on day -1 supported on day 0 by PBSC infusion. Follow-up is now 1–5 months; detailed follow-up data will be available at presentation. Of 37 patients currently evaluable for toxicity, 27 are also evaluable for response. Patient characteristics are outlined in Table 1, depicting a high risk population.
The treatment was administered in the out-patient setting in 37 patients, 27 of whom were entirely managed through ambulatory care. Hospital admission was required for pneumonia in 4, sepsis in 3, nausea and vomiting in 2 and ileus in 1 patient. In 37 evaluable patients, hematopoetic recovery depended upon the timing of PBSC collection (prior to the first, second or the Vel-Mel transplant). Neutrophil recovery to > 1,000/μL occurred at a median of 13 days and platelet recovery to 50,000/μl at a median of 17 days. Non-hematologic toxicities included ≥ grade III mucositis in 5, diarrhea in 11, febrile neutropenia in 5, pneumonia/sepsis in 14, and fatigue in 22 patients. No fatal complications were seen.
Of 27 evaluable patients, partial response (≥ 75% of serum M protein reduction, ≥ 75% of urinary M excretion) was obtained in 9 (39%) including 6 (26%) who showed a complete disappearance of serum M and urine M. Bone marrow follow-up examinations were available in 17 patients and revealed a median reduction in plasmacytosis of 75% including 2 patients achieving a normal bone marrow plasmocytosis
Our results are promising and demonstrate that Vel can be safely added to Mel at doses as high as 250 mg/m2 in fractionated dosing with a high response rate also in high-risk, advanced disease. This approach will be formally evaluated in a randomized trial comparing tandem transplants with Mel 200 mg/m2 alone versus added Vel 1.0 mg/m2 on days 1 and 4 followed on each day by Mel 140 (total 280 mg/m2).
Velcade 1.0 mg/m² Velcade 1.3 mg/m² Parameter Mel 250 Mel 220–240 Mel 200 Mel 100–150 Mel 250 Mel 200 Mel 100–150 N 4 4 12 10 4 2 1 % AGE ≥ 65 0 25 33 30 0 0 100 %Abn Cytogen 75 0 8 30 50 50 0 % Prior Autotx 75 25 33 40 75 0 100 % Prior VTD 50 25 25 30 75 50 100
Gender as a Prognostic Factor in CLL. Biological Pointers to the Improved Outcome of Women.
Authors: Catovsky Daniel , Matutes Estella , Morilla Alison , Burford Anna , Brito-Babapulle Vasantha , Del-Giudice Ilaria , Orchard Jennifer , Oscier David G. , Halsey Jim , Richards Sue 
Published: October 2019

Abstract
Gender is not widely regarded as a prognostic indicator in CLL. However, the combined data from three MRC randomised trials, CLL1, 2 and 3, and two observational studies for patients with Binet stage A, CLL2A and 3A, over a period of 20 years (1978-1998) totalling 2370 patients, showed a significant survival advantage for women (2p<0.0001). Cox regression analysis of the three randomised trials showed that gender, age, stage and response to therapy were independent prognostic variables. The response to treatment for women was also better than for men receiving the same therapies. The LRF CLL4 randomised trial, which started in 1999 shows the same trend. Preliminary results in 444 patients Binet stages A progressive, B and C showed the same CR/Nod.PR for both sexes (43.5%) but a higher PR rate in women (45%) vs men (36.5%) and a lower proportion of women non-responders to first line therapy (11.5% vs 20%). A number of laboratory investigations in CLL4, which included FISH analysis with five probes, VH mutational status, CD38 and ZAP-70 expression by flow cytometry, showed differences between the sexes, which were significant for 17p and 11q deletions combined and CD38, always in favour of women, as shown in Tables 1 and 2.
The clinical and laboratory results suggest that CLL is biologically more benign in women. Women have a lower incidence of CLL, an overall higher incidence of stage A (41.7%) than men (27.3%) in CLL 1, 2, 2A, 3 and 3A and respond better to treatment in all the trials. These differences may be underlined by a higher proportion of 13q del as sole abnormality, a lower proportion of 17p (p53 locus) and 11q deletions and lower levels of CD38. Data on VH mutations and ZAP-70 point in the same direction but the number of cases studied is still small. An additional factor that may play a role in the better outcome for women relates to the effect of oestrogen derivatives which are known to target selectively superoxide dismutase and induce cell kill (Huang et al, Nature407, 390, 2000).
Table 1: FISH analysis by gender (Dohner hierarchical model)
Abnormality 17p del 11q del Trisomy 12 13q del Others * = Combined p value < 0.05 (Chi-Square test) Men (286) 12% 19% 10% 34% 25% Women (94) 7% 13% 11% 44% 25% p value * * 0.052
Table 2: Other biological markers
CD38 negative (<30%) VH mutated ZAP-70 negative Men 173/335 (52% ) 51/149 (34%) 94/192 (49%) Women 68/100 (68%) 23/52 (44%) 42/68 (62 %) p value <0.005 NS 0.07
IV Busulfan (Bu) with Fludarabine (Flu) or Cyclophosphamide (Cy) - Comparing Ablative Conditioning Regimens for Allogeneic Transplantation in AML/MDS.
Authors: de Lima Marcos , Couriel Daniel , Shahjahan Munir , Alamo Jorge , Thall Peter F. , Russell James , Anderlini Paolo , Giralt Sergio , Shpall Elizabeth J. , Jones Roy B. , Champlin Richard E. , Andersson Borje S. 
Published: October 2019

Abstract
As part of our evaluation of Flu as immunosuppressive (and DNA damage repair inhibiting) agent, and as an alternative to Cy in combination with IV Bu, preparing AML/MDS patients for allogeneic transplant (AlloSCT), we postulated that the IV Bu-Flu regimen would yield improved safety, yet increased antileukemic efficacy. We now compared two consecutive series of patients receiving pretransplant conditioning therapy with either IV Bu-Flu or IV BuCy2.
Methods: Flu 40 mg/m2 IV was given once daily, each dose followed immediately by Bu 130 mg/m2 IV over 3 hr (days −6 till −3) (n=128 patients), and in the IV BuCy2 the Bu was given at 0.8 mg/kg over 2 hr every 6 hr for 16 doses (days −7 till −4), followed by Cy 60 mg/kg on days −3 and −2 (n=73 patients). Patients with an unrelated (MUD) or mismatched donor received ATG on days −3 to −1. Graft-versus-host disease (GVHD) prophylaxis was based on tacrolimus and mini-methotrexate.
Patients: Median age was 46 (19–66) (IV Bu-Flu group) and 39 (13–64) (IV BuCy2 group) years, respectively. At transplant 45% and 46% patients were in CR1–3, the remainder had active disease. Cytogenetic risk categories were equivalent for the two groups, with poor or intermediate risk in 88 % in the IV Bu-Flu, and in 82 % of the BuCy2group. Donors were HLA-identical siblings (SIBS) in 53 %, and 73%, MUDs in 39% and 15 %, others in 8 % and 12% respectively. Median follow-up for patients still alive (August 2004) was 15 mos (3–37; n=78) for the IV Bu-Flu group, and 45 mos (24–76; n=27)) for the IV BuCy2 patients.
Results: Both regimens were well tolerated; 100-day treatment-related mortality (TRM) was for SIB/MUD 2.7 / 2% after IV Bu-Flu, and 7 / 9% in the IV BuCy2 group, respectively. Overall, one-year TRM was for 7% after IV Bu-Flu and 18% after IV BuCy2. The overall aGvHD rates were 42% and 45%. 2-year overall survival (OS) were 50% for the IV Bu-Flu group, 42% after IV BuCy2. For patients transplanted in CR the 2-yr OS and event-free survival were 69% and 68 % after IV Bu-Flu, and 48% and 41% in the IV BuCy2.
We conclude, that IV Bu-Flu is a safe and highly effective, reduced toxicity myeloablative conditioning regimen for AML/MDS. Its antileukemic efficacy appears to be at least equal to what is experienced with the IV BuCy2 regimen. Thus, our data demonstrate the IV Bu-Flu regimen to be a new standard for myeloablative conditioning therapy for alloSCT in AML/MDS.
Figure Figure
Impact of Acute GVHD on Immune Reconstitution after Cord Blood Transplantation in Adult.
Authors: Nagamura-Inoue Tokiko , Takahashi Satoshi , Ooi Jun , Tomonari Akira , Iseki Toru , Uchimaru Kaoru , Nagamura Fumitaka , Ohno Nobuhiro , Takasugi Kashiya , Futami Munechika , Uchiyama Michihiro , Soda Yasushi , Konuma Taka-aki , Nakayama Shin , Shioya Mika , Watanabe Nobukazu , Asano Shigetaka , Tojo Arinobu , Takahashi Tsuneo A. 
Published: October 2019

Abstract
BACKGROUND: Immune reconstitution following unrelated cord blood transplantation (UCBT) in adult patients is of great concern because of immaturity of cord blood immunological cells.
STUDY DESIGN AND METHODS: Twenty-six adult patients (15 to 58 year-old) with hematological malignancies, who underwent UCBT and sustained engraftment were enrolled in this study. Infused number of immunological cells in thawed CB units including T cells (CD3+), B cells (CD19+), NK cells (CD3-CD56+), monocytes (CD14+) and also CD34 + cells was analysed using bead-contained TRUCOUNT tube (BD, CA). Dead cells after thawing were excluded by gating out with 7AAD dye. Immune reconstitution was analysed every 30 days by 120 days after CBT. Four-colour FACS Caliber and TRUCOUNT tube were utilized to calculate the absolute number of immune cells concentration in blood after UCBT. We put strict volume of 50μl fresh unmanipulated blood in each TRUCOUNT tube.
RESULTS: Thawed-transplanted NC 2.3±x107/kg, CD34 was 0.72±0.3x105/kg (4.1x106 total), T cells; 3.1±1.6x106/kg with CD4/8 ratio of 3.2±2.0, B cells; 1.2±0.5x106/kg, NK cells; 1.0±0.5x106/kg and monocytes; 1.6±0.6x106/kg. There were no correlations between infused CD34+ cells number and T, B, NK and monocytes numbers. Monocytes increased in blood rapidly after CBT at 30 days, then, declined to the normal value. NK cells was recovered in the early after CBT and then did not so change in number from 30 to 120 days after CBT, while T cells increased time dependent manner, and B cells appeared late but influenced by acute GVHD grade. Within 120 days after CBT, T cells showed also CD4+dominant in most cases with relatively high CD25+CD4+ regulatory T (rT) cells compared to normal control. The patients with grade II to IV aGVHD showed significantly higher number of rT cells on 30 days (P<0.05) compared to those with grade 0–I aGVHD. On day 30, the number of rT cells showed 7.7±5.9/μl in grade 0–I aGVHD and 19.4±13.3/ μl in grade II–IV. The patients with grade II to IV aGVHD showed significant delayed recovery of B cells on 90 days after CBT compared to those with 0–I aGVHD (P<0.001).
CONCLUSION: aGVHD in adult patients may influence on the number of regulatory T cells in the early period after UCBT and delayed recovery of B cells.
MRD-Detection by Multiparametric Flow Cytometry in Childhood Precursor B-Cell All:Predictive Impact of Early Blast Reduction Kinetics in Peripheral Blood (PB) on MRD-Level in Bone Marrow (BM) at Day 33 of the All-BFM2000 Potocol.
Authors: Ratei Richard , Martin Mathilde , Basso Guiseppe , Gaipa Guiseppe , Schrappe Martin , Dworzak5 Michael , Ludwig Wolf-Dieter , Karawajew Leonid 
Published: October 2019

Abstract
Detection of minimal residual disease in childhood acute lymphoblastic leukemia (ALL) has been proven to be of crucial importance for relapse prediction. However, MRD assessment, usually performed at postinduction time points, does not allow early stratification of induction therapy. Here, we address the predictive impact of early blast reduction in pB on BM MRD-levels at the end of induction therapy phase I (d33), quantified by multiparametric flow cytometry (MFC-MRD). Absolute blast cell counts (BCC, blasts/μl) in pB at diagnosis and day 8 as well as MRD-levels in BM and pB at day 15 and 33 were determined in a series of 77 consecutive patients (pts.) enrolled in the AIEOP-BFM-FCM-MRD pilot study (BM d33:MRD+ n=29, MRD- n=48). Blast cells were detected using a two platform method and a 4-color antibody panel with three follow-up tubes:1) CD20-FITC/CD10-PE/CD34-PC5/CD19-PC7, 2) CD58-FITC/CD10-PE/ CD34-PC5/CD19-PC7, 3) CD10-FITC/CD11a-PE/CD45-PC5/CD19-PC7. Additionally, staining with the cell permeant live-cell nucleic acid fluorochrome SYTO 16 combined with CD19 or CD3 and CD45 were used to exclude residual non-nucleated erythroid cells, platelets or debris from absolute blast calculations. We found that BCC in BM and pB at d15 but not at diagnosis and after prednisone prephase at day 8 correlated with MRD-levels in BM at d33 (Spearman correlation coefficient rs=0.41, p<0.001 and rs=0,30, p<0,01). In order to further investigate the impact of early blast reduction between day 0 and day 8 we calculated the relative blast reduction rate on day 8 (BRRd8 = 1-BCCd8/BCCd0). In the group of MRD-negative patients the mean values of BRRd8 were found to be significantly higher than in the group of MRD-positive pts. (98,9% vs. 88,0%, p< 0,05). Moreover, the BRRd8 correlated with MRD-levels in BM at day 33 (Spearman correlation coefficient rs=−0.25, p<0.05). In the current series of pts. maximally selected log-rank statistics were performed for the BRRd8 and the MRD-level in BM at d33 and provided a cut-off value of 97% separating MRD-positive and MRD-negative pts. In conclusion, the assessment of the dynamics of early blast reduction with the parameter of BRRd8 is highly predictive for the outcome of induction phase I of the ALL-BFM2000 protocol.
CD28 Fails to Costimulate Tumor-Specific Activation of Epstein Barr-Virus-Specific Memory Effector T Cells.
Authors: Altvater Bianca , Pscherer Sibylle , Juergens Heribert , Rossig Claudia 
Published: October 2019

Abstract
Genetic modification of cytotoxic T cells with tumor antigen-specific chimeric receptors (chRec) specifically redirects their effector functions towards tumor cells. Integration of the signaling domains of the costimulatory molecule CD28 into chRec enhances antigen-specific proliferation of peripheral blood-derived polyclonal human T cell populations. While CD28 plays an essential role in the priming of naïve CD4+ T cells, its contribution to effector memory cytotoxic T cell (CTL) responses is controversial. We investigated the function of chRec containing the signaling domains of CD28 in vitro expanded T cells with specificity for Epstein-Barr-virus (EBV). Chimeric T cell receptors containing an extracellular single-chain antibody domain directed against the tumor ganglioside antigen GD2 fused to the intracellular signaling domains of both the CD28 and the T cell receptor (TCR) ζ chain (14.G2a-CD28ζ), or TCRζ alone (14.G2a-ζ) were expressed in EBV-specific cytotoxic T cell (CTL) lines from three seropositive donors and in peripheral blood T cells preactivated by CD3-/CD28-specific antibody crosslinking by retroviral gene transfer. Following transduction with the chRec genes, 14.G2a-ζ and 14.G2a-CD28ζ EBV-CTL had comparable levels of chRec surface expression (21–28% versus 26–40%). EBV-CTL had an immunophenotype characteristic of memory effector T cells, coexpressing CD3 and CD45RO in the absence of CD45RA and CD27 surface expression. The transduced CTL maintained their capacity to specifically lyse autologous EBV targets in 4 hr 51Cr release assays and to proliferate after stimulation with autologous EBV targets. Intracellular cytokine staining demonstrated efficient and comparable antigen-specific IFN-γ secretion by both 14.G2a-ζ and 14.G2a-CD28ζ-transduced CTL in response to EBV and tumor targets. Furthermore, GD2+ neuroblastoma targets were lysed in a comparable and antigen-specific manner. However, while antigen engagement by 14.G2a-CD28ζ efficiently induced expansion of non-specifically activated polyclonal peripheral blood lymphocytes in an antigen-dependent manner, CD28 signaling failed to overcome the failure of transduced EBV-CTL to specifically proliferate in response to GD2+ tumor cells. Thus, the costimulatory requirement for the highly efficient proliferative activation response of EBV-specific CTL to viral antigen can not be mimicked by combined CD28 and ζ signaling. Exploring the mechanisms and costimulatory requirements of effector memory T cell reactivation may help to exploit the full potential of this highly cytolytic T cell population for adoptive immunotherapy of cancer.