bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ganciclovir Suppresses Human T Lymphocyte Proliferation In Vitro.
Authors: Battiwalla Minoo , Wu Yiyuan , Nakamura Ryotaro , Radovic Marija , Bajwa Rajinder P.S. , Elefante Anjana , Segal Brahm , Almyroudis Nikolaos , McCarthy Philip L. 
Published: April 2020

Abstract
Clinically significant cytomegalovirus (CMV) infection in allogeneic blood or marrow transplant recipients has dramatically declined in recent years by the strategy of early detection of reactivation and pre-emptive therapy with Ganciclovir (GCV). We have previously shown that even in the absence of overt CMV disease, persisting post-transplant antigenemia predicts for increased late relapse and treatment failure. (Nakamura, et al BBMT 2004) In other words, frequent CMV reactivation serves as a surrogate for impaired post-transplant immune reconstitution. To explain the observed association between CMV reactivation and relapse we also raised the possibility that several weeks of GCV therapy could exert a deleterious effect on a fragile immune system. Clinical association between GCV administration and impaired lymphocyte function has not received attention previously; perhaps because of confounding effects from the underlying conditions (HIV or post-transplant) that induce CMV reactivation. We examined the effect of GCV in vitro on normal human PBMCs. Human PBMCs were extracted from normal volunteers and subjected to mitogenic stimulation (PHA) in the absence or presence of varying concentrations of GCV. PHA-induced proliferation, measured by uptake of 3[H]-thymidine after 5 days incubation in RPMI-10% AB serum, was reduced by 35% at peak therapeutic concentrations (10mg/ml) of GCV as opposed to 73% by Tacrolimus (10ng/ml). GCV did not induce lymphocyte apoptosis in the presence or absence of stimulation. Flow cytometry-based BrdU incorporation assays show that GCV exerts a time-dependent impairment of DNA synthesis in lymphocytes. Collectively, these results show that GCV suppresses T-lymphocyte proliferation in vitro at therapeutic concentrations and the likely mechanism of action is inhibition of DNA synthesis. Further work is ongoing to evaluate the effect of GCV on proliferative responses to specific antigens and to confirm these effects in comparison to other drugs used in the transplant setting.
Figure Figure
Measurement of Minimal Residual Disease (MRD) after Consolidation Therapy as a Means of Early Detection of Relapse in Adult Acute Lymphoblastic Leukemia (ALL).
Authors: Kneba Michael , Brüggemann Monika , Gökbuget Nicola , Reutzel Regina , Hoelzer Dieter , Raff Thorsten 
Published: April 2020

Abstract
Outcome for patients with adult ALL after relapse is poor, even if a second remission is achieved by salvage therapy and is consolidated by an allogeneic stem cell transplantation. There is considerable evidence from studies in childhood ALL and other hematologic malignancies that administration of salvage therapy in early molecular relapse may improve prognosis. We therefore investigated the value of continuous MRD-monitoring in prospectively monitored standard risk patients of the German Multicenter ALL-studies 06/99 and 07/03 during and after maintenance treatment beyond the first year of therapy. MRD was assessed by quantitative realtime PCR using clone-specific primers for the leukemia-specific Ig/TCR gene rearrangements. MRD high risk-patients (those with MRD &gt; 10−4 at two successive time points after induction during the first year of therapy) are candidates for early therapy escalation according to the study protocol and were thus excluded from this analysis. Of the 108 remaining patients (77 male, 31 female), 30 (28%) became MRD-positive again after a median follow-up of 18 months after the end of consolidation treatment. Of these, 17 (57%) already relapsed. When only considering patients with MRD measurable within the quantitative range of the PCR 16/19 (84%) already relapsed. Of the MRD-negative patients only 5 of 78 (6%) have relapsed after a median follow up of 23 month after end of initial therapy. After conversion to MRD positivity, the median time to relapse was 9.5 months, with a median time to relapse of only 2.5 months once the patients’ MRD was within the quantitative range of the PCR assay. Taken together, these data indicate that, if done at regular intervals, MRD-monitoring allows for accurate and timely identification of patients in need for treatment escalation in the vast majority of cases and may help to avoid overtreatment for those patients who are cured by conventional chemotherapy alone.
A Two Step Nonmyeloablative Allogeneic Transplantation Protocol Using In Vitro T-Cell Depleted Mobilized Stem Cells Followed by Donor Lymphocyte Infusions in Patients with Advanced CLL.
Authors: Barge Renee M.Y. , Hoogendoorn Mels , Marijt Erik W.A. , Beaumont Floor , Starrenburg Ingrid , Smit Willem , Posthuma Ward , Fibbe Willem E. , Falkenburg Frederik , Willemze Roelof 
Published: April 2020

Abstract
Transplantation of stem cells that are T-cell depleted using Campath 1H incubation following non-myeloablative (NM-alloSCT) conditioning leads to durable donor engraftment with minimal GVHD using HLA-identical family sibling and unrelated donors. The high levels of donor chimerism allow the subsequent use of DLI to treat residual disease (Exp. Hematol.2003; 31: 865–872). Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. We analyzed 12 patients with advanced CLL (9), PLL (1) or M. Waldenstrom (2) treated with NM-alloSCT. Median age was 56 years. Recipient conditioning consisted of fludarabine (30 mg/m2, 6 days), ATG (10 mg/kg, 4 days) and busulphan (3.2 mg/kg, 2 days). High numbers of G-CSF mobilized peripheral blood CD34+ cells from 11 related and 1 unrelated donors were collected (median 12 x 106/kg). The graft was T-cell depleted by 30 minutes incubation with 20 mg Campath 1H. No post-transplant GVHD prophylaxis was administered. The transplant procedure was very well tolerated. All patients engrafted rapidly. Only 1 patient experienced GVHD gr I (skin) after alloSCT. Sequential chimerism studies of bone marrow showed sustained mixed chimerism with a median donor percentage at 3 months after alloSCT of 86% (range 8–100%). At a fixed time period of 6 months after NM-alloSCT, low dose DLI was administered (5 x 106 CD3+ cells/kg) in 8 patients (3 pts too early after alloSCT and one pt died before DLI). The disease status pre-DLI was persistent disease in 4 pts and CR in 4 pts. After DLI, four patients experienced severe aGVHD (≥ grade 2) and 1 limited cGVHD. Importantly, the observed GVHD after low dose DLI was well managable. One patient received a second transplant from the original donor after myeloablative conditioning due to progressive disease with concommitant decreasing mixed chimerism. Donor chimerism increased after DLI with a median donor percentage of 98% (range, 3–100%) at 3 months after DLI. Presently at a median follow-up of 423 (range 46–1572) days, 9 patients are alive. Four patients are in complete remission, 3 with partial remission and 2 with progressive disease. Three patients have died, two due to infection and one by unknown cause.
In conclusion, in-vitro T-cell depleted NM-alloSCT followed by low dose DLI is a well tolerated strategy in older patients with advanced CLL. The low incidence of GVHD and the high levels of donor chimerism after NM-alloSCT allow the use of DLI to treat residual CLL. Our results demonstrate a profound GVL effect in patients with advanced CLL. NM-alloSCT may prolong survival for this group of patients.
Minimal Residual Disease Monitoring after Reduced Intensity Conditioning (RIC) Allogeneic Transplantation: May Help To Individualize Post-Transplant Immunotherapeutic Strategies.
Authors: Diez-Campelo Maria , Perez-Simon Jose A. , Perez Jose J. , Caballero Dolores M. , Vidriales Belen , Alcoceba Miguel , Vazquez Lourdes , Gonzalez Marcos , Canizo Consuelo M. , Lopez-Berges Consuelo M. , Lopez-Fidalgo D Jesus , Miguel J.F. San 
Published: April 2020

Abstract
We have analyzed the impact of MRD monitoring (detected by flow cytometry) on the outcome of 56 patients undergoing RIC allogeneic SCT. Of them, 67% reached complete remission (CR), 11% partially responded (PR) and 22% progressed or did not respond. MRD assessment after transplant distinguished different risk populations. At day +100, 80% of patients with high MRD levels (&gt;10−2 leukemia asocciatted immunophenotypical cells, LAIP cells) versus 27% of patients with low MRD (&lt;10−4) had relapsed. Accordingly, 3 categories could be clearly idenitified in terms of relapse free survival (RFS) at 5 years: 62% of patients with low MRD levels (&lt;10−4) were event free as compared to only 28% and 20% among patients with intermediate (&gt;10−4 and &lt;10−2) and high MRD (&gt;10−2) (p=0.0047). In multivariate analysis, patients’ age &gt; 60 years (HR: 4,005; 95% CI 1.1–14.1, p=0.03), advanced disease status at transplant (HR: 4,087; 95% CI 1.3–12, p=0.01), failure to develop acute (HR: 4,785; 95% CI 1.2–18, p=0.02) and chronic GVHD (HR: 8,166; 95% CI 2.5–26.1, p=&lt;0.001) and MRD levels, ≥10−4 on day +100 (HR: 5,795; 95% CI 1.7–19.1, p=0.004) adversely influenced RFS. Our study suggests that monitoring of MRD is a useful tool for predicting risk of relapse.
Bortezomib Therapy for Multiple Myeloma in Relapse after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RICT).
Authors: Ducastelle Sophie , Revesz Daniela , Troncy Jacques , Mahmoudi Samira , Thomas Xavier , Thiebaut Anne , Nicolini Franck E. , Tavernier Emmanuelle , Le Quoc-Hung , Chelgoum Youssef , Praire Aline , Michallet Mauricette 
Published: April 2020

Abstract
Multiple myeloma (MM) remains incurable and specially of poor prognosis in case of refractory or relapsed disease. However, recent therapeutic advances including the use of new drugs are promising. Although, Bortezomib, new proteasome inhibitor, has proven its efficacy in patients with refractory or relapsed MM, it has not been sufficiently evaluated in the setting of allogeneic hematopoietic stem cell transplantation. Here, we report four cases of MM patients, very heavily pre-treated and all previously transplanted, who received bortezomib associated to dexamethasone for relapse after allogeneic RICT (median time from diagnosis: 68 months, median time from RICT: 41 months). We studied the feasibility, efficacy and safety of bortezomib: two patients achieved a complete remission, one patient a very good partial response, and one had no response. The tolerance was excellent with only one patient who developed a reversible grade 3 hematological toxicity. No GVHD recrudescence was observed. All patients relapsed after completion of bortezomib treatment. This questions about the potential benefit of maintenance therapy with bortezomib. Given the feasibility and the high efficacy of bortezomib combined with dexamethasone in relapsed MM after RICT, our results argue in favour of an immune-modulatory activity of bortezomib. New strategies combining RICT and bortezomib are warranted to increase and maintain an adequate response. Combination RICT and bortezomib regimen are anticipated to further extend survival in relapsed MM.
The Transcription Factors RUNX1/AML1 and RUNX3/AML2 Protect Bcr-Abl-Transformed B-Cells from Imatinib Induced Apoptosis.
Authors: Miething Cornelius , Grundler Rebekka , Mugler Claudia , Pfeifer Heike , Ottmann Oliver , Barwisch Simone , Speicher Michael , Peschel Christian , Duyster Justus 
Published: April 2020

Abstract
The Abl-tyrosine kinase inhibitor Imatinib efficiently targets the Bcr-Abl kinase and produces major cytogenetic responses in most patients with chronic phase CML. In contrast, patients with advanced stage CML or Ph+ ALL frequently become refractory to Imatinib treatment. Resistance arises predominantly from point mutations in the Abl-kinase region, Bcr-Abl amplification or clonal evolution due to secondary genetic aberrations. To screen for genes contributing to clonal evolution, we have employed retroviral insertional mutagenesis in a murine CML/ALL model to identify potential candidate genes leading to Imatinib resistance. We found proviral insertions near the RUNX3/AML2 promoter in Imatinib resistant leukemic clones, leading to upregulation of RUNX3 mRNA expression. To analyze the effects of high RUNX3 levels on Imatinib response, we expressed RUNX3 in a Bcr-Abl-transformed murine pre-B-cell line. Significantly, whereas there was no effect on Imatinib-mediated proliferation inhibition, the cells displayed a marked reduction of apoptosis. A RUNX3R193A mutant carrying a mutation in the DNA-binding domain of RUNX3 did not protect from apoptosis, indicating that transcriptional regulation by RUNX3 was required to induce the anti-apoptotic effects. To allow for a controlled activation of RUNX transcriptional activity and to extend our analysis to other members of the RUNX family of transcription factors, we constructed 4-OH-tamoxifen (TAM) inducible RUNX3/AML2- and RUNX1/AML1-Estrogen receptor (ER) fusion proteins. These fusion proteins readily translocated from the cytoplasm into the nucleus and activated a RUNX-dependent TCRß-luciferase construct upon addition of TAM. Using these constructs, we could demonstrate that activation of RUNX3 as well as RUNX1 protected Bcr-Abl-transformed Ba/F3 cells from Imatinib-induced apoptosis. Furthermore, we found that RUNX1 mRNA levels were significantly upregulated in patients with Ph+ ALL upon resistance development. Taken together, our data indicate that elevated RUNX3 or RUNX1 levels may contribute to Imatinib resistance in Bcr-Abl expressing leukemic cells.
Tumor Control Achieved Despite Loss of Chimaerism in Renal Cell Carcinoma (RCC) Following Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT): A Case Report.
Authors: Andreola Giovanna , Gigli Federica , Rabascio Cristina , Cazzanti Manuela , Peccatori Fedro , Cinieri Saverio , Pastano Rocco , Martinelli Giovanni 
Published: April 2020

Abstract
The achievement of a mixed chimaerism, which eventually converts to full donor chimaerism, after a non-myeloablative allogeneic PBSCT, is thought to be responsible for a graft-versus-tumor effect to occur. Preliminary data from murine models and haematological malignancies suggest that anti-tumor response can be obtained despite loss of donor chimaerism but, to our knowledge, no such data exist on solid tumors.
On February 2004, V.P, affected by metastatic RCC, already pretreated with a-IFN and Vinorelbine, developed progressive disease in the lung and in the retroperitoneum. On July 2004 she was enrolled in a clinical protocol of reduced conditioning allogeneic PBSCT. Conditioning regimen was the following: fludarabine 30 mg/mq from day −4 to −1, and TBI (2 Gy) on day 0, when she also received 8.53x106 CD34+cells/kg from her sister, HLA-full matched, ABO compatible. aGvHD prophylaxis was performed with micophenolate mofetile 15 mg/kg bid, from day 0 to +27 and cyclosporine (Cys) 5 mg/kg bid, from day −2 to +36, followed by a tapering until +56. Chimaerism evaluation, performed on day +28 and +56, showed a full donor engraftment (&gt;90% donor cells) on bone marrow (BM) samples, with 78% of donor CD3+ T cell on peripheral blood (PB). During follow-up, no signs of aGvHD were observed and CMV p65 and PCR remained negative. On day +90, peripheral pancitopenia occurred: WBC-190/mm3, PLT-8000/mm3, Hb-7.5 g/dL, associated with marrow aplasia. Chimaerism evaluation on both BM and PB showed a graft failure, (&gt;95% recipient cells); serological tests were negative (HCV, parvovirusB19, EBV, CMV and adenovirus), no history of drug interaction could be identified. Because of febrile neutropenia she started a large spectrum antibiotic therapy, G-CSF 5 mg/die and an immunosuppressive therapy with metilprednisolone 1mg/kg plus Cys 5 mg/kg, After 5 days she had recovered the WBC while PLT normalization occurred after 45 days. Cys was continued and stopped at day +210. After a follow-up of 386 days from transplantation, she is still in good general condition, off treatment and with stable disease.
On the basis of murine models, the presence of a sustained SD in an otherwise fatal disease, despite loss of graft may suggest the presence of a host-versus-graftimmune response able to promote anti-tumor responses and may promote the development of novel transplant strategies without the risk of GVHD.
Second Neoplasm after Bone Marrow Transplant (BMT).
Authors: Milone Jorge H. , Napal Juan J. , Bordone Javier A. , Prates Virginia , Garcia Cecilia , Morales Victor H. , Etchegoyen Orlando J. 
Published: April 2020

Abstract
Introduction: the second neoplasm, are pathologies described during the post transplant evolution, often associated to immunosuppression. The post transplant lymphoproliferative syndromes, habitually associated to viruses are the most frequent. The BMT is a procedure clearly different from the rest of the transplants, and this difference would also be observed on the incidence and type of tumor in its evolution.
The incidence of second malignancies after BMT is low, and is related to the use of chemotherapy, particulary alkylating. agents radiotheraphy and immunosuppression.
Objective: To analyze the incidence and characteristics of second neoplasm of the patients undergoing BMT in our Institute.
Results: Between 06/93 and 04/05 over a total of 416 transplants, 132 Allogenic and 284 Autologous, 6 cases of second tumor in variable intervals post procedure were stated.
Table 1.
The data reflects an incidence of second neoplasias of 1,4% (6/416). None of then received radiotherapy in conditioning. No lymphoproliferative syndrome was observed; 2 cases of acute leukemias; being the rest solid tumors with expected evolutions for each pathology.
Table 1 Case Disease Conditioning BMT 2nd Tumor Time betwen BMT-Tumor Evolution 1 MM L-PAM AUTO Lung Cancer 120 months Dead 2 CML BuCy ALLO Colon Cancer 72 months Dead 3 MDS BuCy ALLO Merckel cells tumor 60 months Dead 4 NHL CBV AUTO AML 65 months Dead 5 NHL CBV AUTO Bladder Cancer 58 months Alive 26 months 6 NHL CBV AUTO AML 4 months Dead
Fludarabine/Melphalan Conditioning for Allogeneic Stem Cell Transplantation (SCT) in Elderly Patients with AML/MDS.
Authors: Kennedy Glen A. , Butler Jason , Durrant Simon , Hill Geoff R. , Western Robyn , Morton James 
Published: April 2020

Abstract
Aims: To assess the tolerability and efficacy of a reduced-intensity, non-TBI based allogeneic SCT conditioning regimen utilising fludarabine and melphalan (FluMel) in elderly patients with AML /MDS.
Methods: Fludarabine (25mg/m2 D-7 to D-3) and melphalan (120mg/m2 D-2) allogeneic SCT was performed as part of a prospective phase 2 trial to assess the tolerability of the preparative regimen across a range of haematological malignancies. For this analysis, all patients aged &gt;50yrs with AML /MDS who underwent FluMel transplantation were retrospectively reviewed. Standard GVHD prophylaxis was cyclosporine + methotrexate (D1–11). Both HLA-matched siblings and volunteer unrelated donors (VUD) were permitted as stem cell donors. Graft source was G-CSF stimulated PBPC; all grafts were T-cell replete. Survival data was calculated utilising the Kaplan-Meier product-limit method.
Results: In total 20 patients &gt;50yrs (16M and 4F) had received FluMel allogeneic SCT for AML (n=15) or MDS (n=5). Median age at SCT was 60yrs (range 50 to 67yrs). AML transplants were performed in CR1 (n=5), early 1st relapse (n=3), CR2 (n=3), MDS phase post CR1 (n=2), early 3rd relapse (n=1), and primary refractory disease (n=1); 7/15 AML patients had intermediate risk and 7/15 poor risk cytogenetics (1 no data available). All 5 MDS patients were previously untreated; all had INT-1 risk disease on IPSS. Donors were HLA-matched siblings in 14 cases and VUD in 6. A total of 6 patients have died, including 2 prior to engraftment (1 of hepatic failure and 1 from idiopathic pneumonia syndrome) and 4 after day 75 (relapsed AML 2 cases; acute GVHD 1 case; multi-organ failure 1 case). All 18 patients who survived the initial cytopenic period achieved durable engraftment; 10 (50%) subsequently developed acute GVHD, including grades II-IV in 9 cases (45%) and grades III-IV in 3 (15%). Of the 12 patients with follow-up &gt;3mths post-SCT, 9 (75%) developed chronic GVHD, which was extensive-stage in 8 (67%). At a median follow-up of 2.4 yrs (range 0.1–5.2 yrs), overall and event-free survival at 2 years for the whole cohort are both 66%.
Conclusions: Our experience suggests that allogeneic SCT with FluMel conditioning in elderly patients AML /MDS is associated with acceptable treatment-related toxicity and significant long-term survival. Further studies on this transplant approach in older patients are warranted.
Allogeneic Hematopoietic Cell Transplantation (HCT) for Acute Leukemia in First Relapse or Second Remission.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Lee Young-Shin , Yun SungCheol , Yoon Sung-Soo , Kim Inho , Park Seonyang , Kim Byoung Kook , Jung Chul Won , Kim Kihyun , Ahn Jin Seok , Lee Kyoo-Hyung 
Published: April 2020

Abstract
Allogeneic HCT offers the best chance for long-term survival in patients with acute leukemia after first relapse. A difficult clinical decision for a patient suffering leukemic relapse who has a histocompatible donor is whether to attempt re-induction therapy or proceed directly to HCT. Sixty-five patients with acute leukemia in first relapse or second remission were treated with allogeneic HCT at 3 institutes in Seoul, Korea between Jan 1995 and Sep 2004. We analyzed their post-transplant outcomes and investigated the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT. Forty patients received hematopoietic cell graft from a sibling donor, 21 from an unrelated donor, and 2 from a haplo-identical family donor, and 2 received cord blood. Thirteen patients received TBI-based conditioning regimen and 10 received reduced-intensity conditioning regimen. There occurred 34 relapses with 51.3% of 5-y cumulative incidence of relapse (CIR) and there were 22 non-relapse deaths with 34.7% of non-relapse mortality. Probabilities of overall survival and disease-free survival were 20.6% and 14.0% at 5-y, respectively. Multivariate analysis by Gray method for CIR revealed that patients with unfavorable cytogenetics (Philadelphia chromosome-positive or complex karyotype) and those not in remission at the time of HCT had significantly higher CIR (P=0.023 and P=0.031, respectively). Fourteen patients underwent allogeneic HCT after first relapse without salvage chemotherapy aimed at re-induction of remission (“untreated relapse”), 15 patients failed in attempts aimed at re-induction of remission before HCT (“refractory relapse”), and 36 patients attained second remission with salvage chemotherapy before HCT (“second remission”). 5-y CIR for “untreated relapse” (57.1%) was higher than that for “second remission” (42.3%), but lower than that for “refractory relapse” (66.7%). Among patients transplanted in relapse, those with BM blasts ≤ 30% seemed to have lower 5-y CIR than patients in florid relapse (BM blasts &gt; 30%) (57.7% vs. 70.6%). These results do not support the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT in patients with acute leukemia after first relapse. At least the patients with early relapse do not appear to receive benefit from salvage chemotherapy before HCT.