bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II, Open Label Study of AT-101 in Combination with Rituximab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia.
Authors: Castro Januario E. , Olivier Loria J. , Robier Aguillon A. , Danelle James , Carlos Suarez J. , Bi-Ying Yeh , Thomas Kipps J. 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) cells express high-levels of Bcl-2 and related anti-apoptotic proteins that collectively can enhance leukemia-cell survival and drug-resistance. AT-101 is an orally active BH3-mimetic that can inhibit the anti-apoptotic activity of Bcl-2-family-member proteins (e.g. Bcl-2, Bcl-XL, Mcl-1) and induce CLL cells to undergo apoptosis. Furthermore, we found that AT-101 also can enhance the cytotoxicity of rituximab for CLL cells in vitro. As such we conducted a phase 2 trial to evaluate the safety and activity of AT-101 when used together with rituximab to treat 12 patients who had relapsed/refractory CLL. Patients received AT-101, at 30 mg/d, for 21 or 28 days during each of three 28-day cycles. Rituximab was administered at 375 mg/m2 for 12 doses (total dose = 4,500 mg/m2) on days 1, 3, 5, 8, 15, 22, 29, 31, 33, 40, 57, 59, 61. The first dose of rituximab was given over two days to minimize infusion-related adverse events. The patients’ median age was 61.5 years (range 43–81). Nine patients were high risk and 3 were intermediate risk based on the modified Rai classification and had received a median of 2 prior regimens (range 1–8). Six patients had leukemia cells that expressed ZAP-70 and/or unmutated immunoglobulin variable region genes and 4 patients had either 11q deletions or complex cytogenetics. Six patients interrupted treatment due to adverse events, most of which were transient and without residual complications. Grade 1–2 gastrointestinal effects (e.g., nausea, vomiting) occurred in 11 patients, 2 of whom had grade 3/4 ileus. Six patients experienced treatment-associated fatigue (grade 1–2 in 5 and grade 3 in one). Other than ileus and fatigue the only grade 3/4 event noted was neutropenia. One patient without neutropenia died while undergoing treatment from community-acquired bacterial pneumonia[j1]. Pharmacokinetic studies demonstrated that the average Cmax of AT-101 was 565 ng/ml (280 – 805 ng/ml) at a Tmax of 3.1 hours (1.7 – 5.6 hrs.). Correlative science studies performed on leukemia cells isolated at various times after treatment demonstrated leukemia-cell apoptosis in vivo, with maximum levels seen at times when we observed peak drug levels of AT-101. Eight patients had completed the study and had full response evaluation at the time of this abstract’s submission. The overall response rate was 38% [CRu (2); PR (1); SD (3); PD (2)]. Four of eight patients (50%) had significant reductions in leukemia cell counts and splenomegaly and 5 of 8 (63%) had reductions in lymphadenopathy. AT-101 in combination with Rituximab has apparent activity in patients with relapsed-refractory high-risk CLL. Additional enrollment is planned using alternate AT-101 schedules in an attempt to increase peak plasma concentrations (and potentially activity) and reduce GI toxicity.
Risk Factors for Late Infections after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Related Donor.
Authors: Robin Marie , Porcher Raphaël , De Castro Araujo Renato , de Latour Régis Peffault , Devergie Agnès , Rocha Vanderson , Larghero Jérome , Espérou Hélène , Adès Lionel , Gluckman Eliane , Ribaud Patricia , Mary Jean-Yves , Socié Gérard 
Published: October 2019

Abstract
After allogeneic hematopoietic stem cell transplantation (HSCT), late infections represent a major cause of morbidity and mortality but little has been previously reported. In a retrospective cohort study, late infections incidence was determined in 196 long-term survivors after matched related HSCT. Only patients transplanted for aplastic anemia, chronic myeloid leukemia (CML) and acute myeloblastic leukemia (AML) were included in this study. Median follow-up was 8 years. Among 30 patients who died beyond the first year, 9 patients died from graft-versus-host disease (GVHD) and 10 from infections. Bacterial late severe infections occurred in 30 patients, yielding an 8-year cumulative incidence of 15%. Late invasive fungal infection occurred in 8 patients corresponding to a cumulative incidence of 3.6%. Most viral infections were hepatitis C and VZV and overall late viral infection incidence was 35%. We identified 3 risk factors for bacterial infections in multiple analysis: CMV status (positive recipient and negative donor), irradiation based conditioning regimen and extensive chronic GVHD within the first year. Extensive chronic GVHD was the only risk factor of non-HCV viral infection in patients transplanted for AML or CML. Thus, late life threatening infections may occur in nearly a fourth of late survivors even after matched related transplantation and are associated not only with chronic GVHD but also with irradiation and to CMV status prior to transplantation.
Lung Resection for Invasive Pulmonary Aspergillosis in Neutropenic Patients with Hematologic Malignancies: Long Term Results in Thirty Two Cases.
Authors: Gastinne Thomas , Touzeau Cyril , Vigouroux Stéphane , Le Gouill Steven , Mahé Béatrice , Dubruille Viviane , Delaunay Jacques , Chevalier Patrice , Guillaume Thierry , Sagan Christine , Gay-Andrieu Françoise , Germaud Patrick , Despins Philippe , Moreau Philippe , Harousseau Jean-Luc 
Published: October 2019

Abstract
Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in neutropenic patients. Despite adequate medical treatments, such as amphotericin B or voriconazole, the prognosis of IPA remains poor. Nevertheless, recent studies suggest that the outcome of IPA is improving due to early diagnosis (CT scan, antigenemia), use of new antifungal agents (Azols and Echinocandins), and possibly in some cases to early surgical resection. We here report a retrospective one center study of 32 cases of IPA treated by surgical treatment from 1988 to 2005.
Between 1988 and December 2005, thirty-seven consecutive patients underwent lung resection for suspected IPA. They were 22 men and 15 women, with a median age of 49.2 years (15 – 74). The underlying diseases were AML, ALL, aggressive lymphoma and myeloma in 26, 7, 2 and 2 cases, respectively. Surgery was planned after hematologic recovery from the last course of chemotherapy during which IPA was diagnosed, either possible in 18 cases, probable in 18 cases or proven in 1 case (Ascioglu, CID 2002). Surgery consisted in 1 pneumectomy, 6 bilobectomies, 18 lobectomies, 8 wedge resections and 4 lobectomies with wedge resections. No perioperative deaths occurred and the median duration of post surgical hospitalisation was 13 days. Six patients presented surgery related complications: three patients required prolonged pleural drainage, one had a section of the phrenic nerve, one presented a major bleeding and last patient had a pneumopathy. The diagnosis of definite IPA was confirmed in 32 cases. Immediately after surgery, 26 of the 32 patients were able to receive subsequent intensive chemotherapy courses, including 15 stem cell transplant (SCT), either auto (5) or allogenic (10). In all cases, patients subsequently received parenteral antifungal therapy. During these new intensive chemotherapy courses, recurrent aspergillosis was observed in only 2 cases, inducing 1 death from brain localization. Overall, with a median follow-up of 8.3 years (1–18), 40.5% of the patients are alive and the main cause of mortality was relapse, but not IPA.
In conclusion, early surgical resection together with antifungal therapy allows definite diagnosis of IPA, prevents from IPA recurrence and early death due to hemotysis, with very few peri-operative complications. All the more, it allows subsequent high-dose chemotherapy to treat the underlying hematologic disease. Surgery might be a treatment of choice to a define group of patient.
Tacrolimus Versus Cyclosporine for Graft-Versus-Host Disease Prophylaxis in Pediatric Patients Undergoing Matched Unrelated Donor Hematopoietic Stem Cell Transplants. A Pediatric Blood and Marrow Transplant Consortium Study..
Authors: Atlas Mark P. , Yanik Gregory , Goyal Rakesh 
Published: October 2019

Abstract
Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. In the adult literature tacrolimus was demonstrated superior to cyclosporine in preventing grade II–IV acute GVHD in both related and unrelated donor transplants; however, there is no data comparing their efficacy in the pediatric population. In a multi-institutional trial, we prospectively evaluated the clinical data on 102 patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 59.8% of patients received cyclosporine and 40.2% of patients received tacrolimus. Rates for maximum grade II–IV acute GVHD were 37.7% for cyclosporine and 39% for tacrolimus (p = 0.89). Rates for maximum grade III–IV acute GVHD were 19.6% for cyclosporine and 24.4% for tacrolimus (p = 0.57). Incidence of chronic GVHD in 97 evaluable patients was 37.9% in 58 patients who received cyclosporine and 35.8% in 39 patients who received tacrolimus (p = 0.84). Survival at 1 year post-transplant was similar in both groups: 59.2% for cyclosporine and 51.2% for tacrolimus (p= 0.31). Toxicity analysis is ongoing. In pediatric matched unrelated donor transplantation, the efficacy of tacrolimus/methotrexate and cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.
Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).
Authors: Platzbecker Uwe , Pabst Caroline , Kiani Alexander , Schetelig Johannes , Wermke Martin , Helwig Anett , Ehninger Gerhard , Bornhäuser Martin 
Published: October 2019

Abstract
Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML.
Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS.
Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission.
Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.
Low Incidence of Cytomegalovirus Infection Associated with Rapid Cell-Mediated Immune Reconstitution after Cord Blood Transplantation Using Full Conditioning Regimen Containing 12Gy Total Body Irradiation.
Authors: Takahashi Satoshi , Ooi Jun , Tomonari Akira , Tsukada Nobuhiro , Konuma Takaaki , Kobayashi Takeshi , Sato Aki , Tojo Arinobu , Watanabe Nobukazu , Nakauchi Hiromitsu , Asano Shigetaka 
Published: October 2019

Abstract
The one of crucial questions in cord blood transplantation (CBT) is whether naïvity of cord blood lymphocytes could gain antigen-specific cellular immunity during early phase of transplant. Cytomegalovirus (CMV) infection is serious clinical problem in allogeneic transplant recipients and T cell immunity has known to have an important role in control of virus replication and prevention.
During 1998 and 2006, 111 adults has received myeloablative regimens including 12 Gy of total body irradiation followed by CBT and a standard cyclosporine and methotrexate combination as GVHD prophylaxis in our institute. Patients also received intravenous immunoglobulin from day −3 to day 120 if the immunoglobulin level in the serum was less than 500 mg/dl. CMV antigenemia assay was performed twice a week after neutrophil recovery until day 120. Once CMV antigenemia is positive, patients received 5 mg/kg ganciclovir (GCV) once daily for at least 2 weeks as preemptive therapy. Ninety-two patients achieved engraftment with full donor chimerism and survived without disease relapse at the time of 120 days after CBT (82.8%). None of these 92 recipients had CMV disease during first 4 months after CBT.
We have investigated the association of CMV reactivation status and their immune reconstitution process for 4 months after CBT in 39 patients who received CBT from 2002 to 2006 in our institute. CMV-specific CD4+ and CD8+ T cell recoveries were assessed by detection of interferon-g (IFN-g) producing cells with CMV antigen stimulation using intracellular cytokine staining. The positive was defined as more than 0.1% IFN-g positive cells among CD4+ or CD8+ T cell population.
Six of 39 patients were CMV sero-negative and 33 patients were sero-positive. None of 6 CMV sero-negative receipients and 31 of 33 CMV sero-positive recipients observed CMV reactivation and received GCV therapy within the first 4 months.
CMV-specific CD4+ T cells were detected in 30 of 31 recipients with positive CMV antigenemia (% positive: 55% at 1 month and 85% at 2 month), on the other hand, CMV-specific CD8+ T cells were detected in 14 out of 31 cases (% positive: 14% at 1 month and 22% at 2 month), both of which were comparable to post-bone marrow or peripheral blood transplants (CMV-specific CD4+ T cells were detected 18 of 21 recipients with positive CMV antigenemia and CMV-specific CD8+ T cells were detected in 12 out of 21).
These data suggest that post-thymic naive T lymphocytes in cord blood might obtain memory and effector function in vivo with antigen-specific manner during early phase of post-transplant.
Generation of Multi-Specific CTL Lines Using Overlapping Pentadecapeptide Pools of Aspergillus f16 and Adenovirus Hexon Antigens Presented on Epstein Barr Virus-Transformed B Cells as Antigen Presenting Cells.
Authors: Zhu Fenlu , Davies Barbara , Margolis David A. , Keever-Taylor Carolyn A. 
Published: October 2019

Abstract
Allogeneic hematopoietic progenitor cell transplantation (HPCT) is the optimal treatment for several hematological malignancies, aplasia or other disorders of the hematopoietic or immune system. Post HPCT, patients undergo a prolonged period of immune incompetence during which they are highly susceptible to viral and fungal infections. Epstein Barr Virus (EBV), Adenovirus (Ad) and Aspergillus fumigates are among the most common and lethal infections during this period. We have described the use of overlapping pools of pentadecapeptides pulsed onto monocyte-derived dendritic cells (DC) to generate cytolytic T-cell (CTL) lines specific for an A. fumigatus-derived antigen, Asp f16 (Ramadan et. al., 2005, J Clin Immunol139:257; Ramadan et. al., 200 J Clin Immunol 140:81). We have further demonstrated in 5 donors, the generation of CTL lines recognizing peptides contained within the conserved region of the Adenovirus hexon protein using a similar approach (Keever-Taylor, et. al, Cytotherapy 8, Suppl 1, 122). To reduce the need for large numbers of DC to prime and expand the CTL cultures, we modified our procedures to use peptide pool (pp)-pulsed EBV-transformed B lymphoblastoid cell lines (BLCL) as antigen presenting cells (APC) following 2–3 rounds of initial priming with pp-DC. This approach results in lines that are predominately reactive to Asp f16 or Ad hexon, and which are moderately reactive to EBV. We expanded our studies to determine the feasibility of generating CTL lines that recognize all three infectious agents. Peripheral blood lymphocytes (PBL) from donor RD0309 were primed weekly ×3 with autologous DC (10:1 PBL to DC ratio) pulsed with a pool of both Asp f16 (104 individual peptides) and Ad hexon (105 individual peptides) pentadecapeptides, then switched to Asp/Ad-pulsed BLCL as APC. The cultures were screened one week following restimulation for lysis of non-pulsed (np-BLCL) and Asp f16-pp-pulsed (Asp-BLCL) and Ad hex-pp-pulsed (Ad-BLCL) BLCL targets. Weak reactivity to Ad-BLCL was detected after 3 primings with DC alone that increased following one round of Asp/Ad-BLCL priming. Asp f16-specific CTL activity was not clearly detected until one week after 3DC plus 3BLCL primings, at which time there was also clear reactivity to np-BLCL targets (26.4% np-BLCL, 37% Asp-BLCL, and 53.9% Ad-BLCL at 50:1), indicating CTL activity to all three infectious agents. With an additional priming, Aspergillus specific reactivity exceeded that towards Adenovirus and EBV-specific reactivity declined. These data show that a pool of overlapping peptides from two different antigens presented on DC followed by BLCL as APC can result in multi-specific cell lines that can be potentially used in adoptive immunotherapy protocols for the treatment or prevention of common opportunistic infections following HPCT.
Determination of a Limited Sampling Strategy for IV Busulfan Dose Individualization in Children.
Authors: Sibbald Cathryn , Schecter Tal , Doyle John , Dupuis L. Lee 
Published: October 2019

Abstract
Busulfan doses are individualized in order to achieve an area under the plasma Busulfan concentration vs time curve (AUC) to ensure engraftment while preventing hepatic venous occlusive disease. We currently calculate AUC using 7 plasma Busulfan samples drawn after the first of 16 Busulfan doses given every 6 hours. The objective of this retrospective study was to evaluate the extent of agreement between the AUC calculated using 7 plasma Busulfan concentrations (AUC-7) and each possible limited sampling strategy (LSS) in children undergoing haematopoietic stem cell transplant. 44 children aged 0.3 to 16 years (median: 3.0 years) received IV Busulfan from April 1, 2003 through January 2006 at our institution. Busulfan doses given and subsequent plasma Busulfan concentrations were recorded for each patient. AUC-7 and AUC using all possible LSSs were calculated using non-compartmental and 1-compartmental methods (WinNonLin version 5.0.1). Based on a target AUC of 1300 micromole·min/L, a theoretical adjusted Busulfan dose was calculated using AUC-7 and all LSSs using 2 and 3 plasma Busulfan concentrations. Extent of agreement betweenthe AUC-7 values and the LSS AUC values andthe theoretical adjusted Busulfan dose based on the AUC-7 values and the 2 and 3 point LSS AUC values was assessed by determination of the intraclass correlation coefficient (ICC; parallel, one-way random effect model) and Bland-Altman (BA) analysis.
Agreement was observed between AUC-7 calculated using non-compartmental and 1-compartmental methods and LSSs using 2 and 3 plasma Busulfan concentrations. AUC values calculated using 6 LSSs each consisting of 3 plasma Busulfan concentrations achieved ICC values > 0.96 (p<0.001) and were within the BA limits of agreement. Agreement between the theoretical Busulfan adjusted doses (7-point vs 3-point strategies) was very strong when the Busulfan concentrations obtained at the following time points were used: end of the 2 hour infusion, 3, and 4 hours after completion of the infusion; or 0.25, 3, and 4 hours after completion of the infusion. We conclude that there is excellent agreement between AUC-7 and a LSS for calculation of Busulfan AUC using 3 time points andbetween theoretical adjusted Busulfan doses calculated using AUC-7 and using these strategies.
The LSSs described here must be validated in a prospective study.
Retransplantation with Stem Cells from Mismatched Related Donors after Graft Rejection in Pediatric Patients.
Authors: Lang Peter J. , Greil Johann , Müller Ingo , Bader Peter , Klingebiel Thomas , Heinzelmann Frank , Belka Claus , Kremens Bernhard , Reiter Alfred , Schlegel Paul G. , Handgretinger Rupert 
Published: October 2019

Abstract
Graft failure is a rare but life-threatening complication after transplantation of hematopoietic stem cells. Treatment comprises immunoablative reconditioning regimens and a second stem cell donation from the same or from a different donor as soon as possible to minimize the time of pancytopenia and its sequelae.
We report a cohort of 11 pediatric patients with leukemias (acute lymphatic n=4, acute or chronic myeloic/MDS n=4) and severe aplastic anemia (n=3) who experienced graft rejection after TBI, busulphan or melphalan based myeloablative transplantation from mismatched related donors (MMRD) (n=6) or after cord blood/matched unrelated donor (MUD) transplantation (n=5) between 2000 and 2006. In the latter the original donor was not available a second time. Thus, all patients were re-transplanted with CD34+ positive selected or CD3/CD19 depleted stem cells from a second, haploidentical parental donor (MACS method, Miltenyi Biotec). Median time span from diagnosis of graft rejection to second donation was 16 days. The reconditioning regimens consisted of total lymphoid irradiation or cyclophosphamide, thiotepa (5mg/kg), fludarabine (120 mg/m2) and ATG/OKT3. A median number of 25×106/kg of body weight stem cells with 60.000/kg residual T cells were infused. Mofetilmycophenolat was given as GvHD prophylaxis, if residual T cells exceeded 25 000/kg bw. Sustained engraftment was achieved in all patients (ANC>500/μl: 9 (11–32) days). No GvHD > grade II was observed. T cell recovery was delayed, however no lethal viral infection occurred. Severe organ toxicity was observed in 2 patients (BOOP, hemorrhagic cystits) and moderate mucositis in 11 patients. 8/11 patients are disease free (median follow up 1.5 (0.3–6.6) years; 1 year EFS=73%). Causes of death were: BOOP (n=1), infection (n=1); only one patient with refractory AML relapsed. Thus, transplantation of stem cells from haploidentical donors represents a realistic option to rescue patients with graft failure within a short time span and for whom a second donation of the original donor is not available. The use of a different donor may help to avoid a second rejection.