bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Term Survival of Patients with Chronic Myelocytic Leukemia after Allogeneic Stem Cell Transplant Using a Reduced Intensity Regimen of Melphanlan, Lomustine and Cyclophosphamide.
Authors: Jia Yongqian , Liu Ting , Niu Ting , Xu Caigang , Meng Wentong , Lu Jianchun , Wang Hui 
Published: April 2020

Abstract
Introduction: Non-ablative regimens have been shown to be effective and less toxic than traditional ablative regimens, but they usually need close monitoring and skillful manipulates e.g. donor lymphocyte infusions. In the present study, we used a novel reduced intensity regimen with melphanlan, lomustine and cyclophosphamide to treat patients with chronic myelocytic leukemia and made a long term follow-up.
Methods: 14 patients with median age of 35(23~52) were treated with MCC regimen(Melphanlan 170 mg/m2/d×1, Lomustine 400 mg/m2/d×1, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 6 years; another 16 patients with median age of 33(16~44) were treated with BuCy regimen(Busulfan 4 mg/kg/d×4, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 4 years.
Results: All the patients were engrafted successfully and the platelet recovery to 20×109/L was earlier at median 3 days in patients with MCC regimen. 4 of 10 patients examined in MCC group showed mixed chimerism at day 100 post transplant, whereas only 1 of 12 patients examined in BuCy group showed mixed chimerism. All the patients became complete donor sources later without any DLI. The regimen related toxicity was relatively lower in MCC group, especially the incidence and severity of mucositis and liver dysfunction were decreased significantly. The median duration of hospitalization was 39 days (25~55)for patients with MCC regimen, and 55 days (39~90) for BuCy regimen. The 5 year disease-free survival was 71.4% for MCC group and 62.5% for BuCy group, respectively. The transplant related mortality and relapse rate were 21% and 7% for MCC regimen, whereas 25% and 12% for BuCy regimen.
Conclusions: MCC regimen is an effective and less toxic conditioning regimen and the long term disease-free survival is as the same as that of BuCy regimen. Considering the cost-effect efficacy, MCC regimen may have some prominent advantages over BuCy regimen.
Figure Figure
Target Dose Adjustment of Oral Busulfan Using a Test Dose in Japanese Adults Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Takamatsu Yasushi , Ogata Kentaro , Sasaki Noriaki , Hara Shuuji , Eto Tetsuya , Kato Kouji , Nagafuji Kouji , Abe Yasunobu , Kubota Akira , Choi Ilseung , Imamura Rie , Imamura Yutaka , Taira Naoya , Suzumiya Junji , Tamura Kazuo 
Published: April 2020

Abstract
Oral busulfan (BU) is widely used in patients undergoing hematopoietic stem cell transplantation (HST). Therapeutic effect of BU is related to the area under the plasma concentration-time curve (AUC) or the average plasma concentrations at steady state (Css). It has been shown that BU pharmacokinetics (PK) are highly variable and the dose adjustment according to the BU levels is critical to get the successful results of HST for Caucasians. BU is metabolized mainly in the liver through conjugation with glutathione by glutathione S-transferase (GST). Recent study has shown that the polymorphisms of GST genes are associated with the risk of developing hepatic veno-occlusive disease in patients undergoing HST. Ethnic variation is also demonstrated in relation to a gene deletion polymorphism of GST, suggesting that BU metabolism is influenced by the race. BU PK have been extensively investigated in Caucasians and few studies have focused on Asian people. We therefore underwent a prospective trial of adjusting BU doses depending on the individual BU PK in 36 Japanese patients aged from 16 to 64 years (median; 47 years). All patients received a busulfan-containing conditioning regimen and underwent allogeneic HST. Individual PK were studied following a 0.5 mg/kg test dose of BU administered orally. BU concentrations were measured by a high-performance liquid chromatographic method and individual PK parameters of BU were calculated with a one-compartment model by using Bayesian modeling program. The median clearance (CL/F) was 0.16 L/hr/kg (0.09 to 0.34 L/hr/kg), the median volume of distribution (Vd/F) 0.65 L/kg (range; 0.41 to 0.97 L/kg), the median elimination half-life (t1/2) 2.9 hr (range; 1.9 to 7.0 hr), and the median absorption rate constant (ka) 2.46 /hr (range; 0.53 to 6.03 /hr). BU doses were adjusted to achieve a target BU Css between 800 and 900 ng/mL. Twenty-six (72%) patients were required to reduce BU doses and adjusted BU doses ranged from 0.51 to 1.29 mg/kg/time (median; 0.85 mg/kg/time). After administrating the 6th dose of BU for the conditioning regimen, BU PK were analyzed. Expected Css was significantly correlated with observed Css and predictability of the test dose was 106.4±21.8%. Engraftment was successful in 34 of 36 (94%) patients. Grade 2 to 4 regimen-related toxicity except stomatitis occurred in 4 (11%) patients. These data demonstrate that BU PK vary widely from one patient to another after oral BU in Japanese and individualization of BU doses depending on the BU PK are useful in improving clinical outcome in patients undergoing HST.
Intravenous Busulfan Dosed Once Daily or Four Times Daily as Part of the Standard BuCy Preparative Regimen for Allogeneic Stem Cell Transplantation.
Authors: Shaughnessy Paul J. , Bachier Carlos , Alexander Lorraine , LeMaistre C. F. 
Published: April 2020

Abstract
Intravenous busulfan (IVBu) (Busulfex ESP Pharma) is regularly substituted for oral busulfan as part of the standard busulfan and cyclophosphamide (BuCy) preparative regimen for allogeneic stem cell transplantation (ASCT). Oral busulfan was originally dosed 4 times daily, which led to the current accepted dosing schedule for IVBu. Pharmacokinetics (PK) and busulfan clearance allow for once daily dosing now that IVBu is available. We performed a retrospective review of 36 consecutive patients who received the BuCy preparative regimen with IVBu prior to ASCT. Twenty-one males and 15 females with a median age of 46 years (23–64) were treated for AML (n=15), ALL (n=1), CML (n=8), MDS (n=8), NHL (n=2), and multiple myeloma (n=2). IVBu was dosed 0.8 mg/kg 4 times daily for 16 doses (n=16) or 3.2 mg/kg once daily for 4 doses (n=20) on days -7 to -4, and cyclophosphamide was dosed 60 mg/kg once daily for two doses on days -3 and -2. IVBu was dosed by ideal or adjusted ideal body weight and no PK studies were done. Bone marrow (n=6) or peripheral blood (n=30) stem cells were infused on day 0 from HLA matched siblings (n=26) or unrelated donors (n=9), and one partially matched unrelated donor. Engraftment occurred in 34 patients (pts) (94%). Two pts who failed to engraft had bone marrow grafts with low numbers of total mononuclear cells infused. Regimen related toxicity (RRT) included mild VOD in 2 pts (5%) that self resolved, with one pt receiving IVBu 4 times daily and the other once daily. There was no seizure activity or non-infectious interstitial pneumonitis attributed to RRT in any patient. Other RRT were not significantly different between the patients who received 4 times daily or once daily IVBu. For all patients day 100 mortality was 17%, and at a median follow up of 12 months (1–54) 17 pts (47%) survive. Five of 16 pts (31%) survive who received 4 times daily IVBu, and 12 of 20 pts (60%) survive who received once daily IVBu. Three patients received once daily IVBu as outpatients and no patients received 4 times daily IVBu as outpatients. Financial review between day -7 to day 0, days 1–30, days 61–90, and day-7 to day 90 revealed patient charges were not significantly different at these time points between the once daily and 4 times daily dosing groups. In conclusion, this small retrospective single institution study revealed IVBu dosed once daily by ideal or adjusted ideal body weight appeared to have similar RRT, engraftment, survival and cost compared to 4 times daily IVBu when used as part of the BuCy preparative regimen for ASCT.
Cytokine Gene Expression in Peripheral Blood Mononuclear Cells Points to Interleukin-10 as an Inhibitor of Alloreactivity Following Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning.
Authors: Petersen Soren L. , Madsen Hans O. , Ryder Lars P. , Svejgaard Arne , Dickmeiss Ebbe , Vindelov Lars 
Published: April 2020

Abstract
Cytokines are thought to play an important role in the pathophysiology of Graft-versus-Host disease (GVHD). To study the relationship between cytokines and GVHD, we obtained peripheral blood mononuclear cells (MNC) from 21 patients with hematologic malignancies and their human leukocyte antigen identical sibling donors before and sequentially after hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning. The MNC were cultured for 72 hours either alone or in mixed lymphocyte cultures with irradiated MNC of recipient, donor or HLA-mismatched third-party origin. The gene expression of interleukin (IL)-2, IL-4, IL-10, IL-18, tumor necrosis factor-α and transforming growth factor-β in each culture was then measured by real-time quantitative RT-PCR. The composition of the responder MNC differed between patients and donors and changed following HCT with a possible influence on the results. Early after transplant (day +14) the IL-10 mRNA level in response to recipient or donor antigens was higher in patients who did not develop clinical significant acute GVHD when compared to the level in patients who subsequently developed acute GVHD grades II–IV (p=0.005 and p=0.004, respectively). The IL-10 mRNA level on day +14 was highly correlated to the pre-transplant mRNA level of the recipient MNC but not to the level of the donor MNC, suggesting that the IL-10 mRNA detected on day +14 originated from responder cells of recipient origin. A higher IL-10 mRNA level was found in MNC obtained pre-transplant from recipients who progressed or relapsed after the transplant when compared to the level in patients who did not, p=0.03. In conclusion we find that detection of cytokine gene expression in MNC by real-time quantitative RT-PCR is an interesting tool in the study of the immune responses following HCT. A number of factors are likely to influence the results obtained and in this study we have identified the composition of the MNC as such a factor. Our results suggest a role for IL-10 as an inhibitor of alloreactivity following nonmyeloablative HCT. This inhibition may have dual effects by limiting the degree of acute GVHD and at the same time increase the probability of relapse.
Late Onset Neutropenia and Decreased Immunoglobulin Concentration after Rituximab Combined Autotransplantation for B Cell Lymphoma.
Authors: Hirayama Yasuo , Kohda Kyuhei , Hirata Yasuji , Kuroda Hiroyuki , Matsunaga Takuya , Konuma Yuichi , Yoshida Makoto , Sakai Toshiro , Niitsu Yoshiro 
Published: April 2020

Abstract
Chemotherapy with Rituximab is widely used to treat patients with various B-cell lymphomas and auto-transplantation with Rituximab is promising strategy due to the potential for in vivo purging. However, the possibility of late onset neutropenia and immunoglobulin suppression after auto-transplantation with Rituximab has been indicated. We studied the frequency and degree of these phenomena. We performed a retrospective analysis on 26 consecutive patients at three centers during the period of January 1998 to March 2005.
Thirteen patients (Follicular 8, Marzinal zone B cell lymphoma 2, Diffuse large B 3) received auto-transplantation without Rituximab (R-) compared with 13 patients (Follicular 8, MZBCL 2, DLB 3) received auto-transplantation with Rituximab (R+). In R+ patients pripheral blood stem cells were harvested after High dose AraC followed by three times of Rituximab (375mg/m2 day -2 of AraC, day7, 14). Conditioning regimen consisted of MCEC (MCNU, CBDCA, ETOP, Cy) or TBI+Cy followed by three times of Rituximab (375mg/m2 day 0, 7, 14).
Mean immunoglobulin concentration one month after transplantation was 890 mg/dl for R- vs. 470 mg/dl for R+ (P=0.04). Lowest neutrophil numbers over 4 weeks after transplantation was 1.24X109/L for R- vs. 0.36X109/L for R+ (p=0.02). Late onset neutropenia (&lt;0.5X109/L) were seen in three cases of R+ group, but no case in R- group. Therapy related death was seen one case in R+ group. This case showed low immunoglobulin level after transplantation and died of Pneumocystis Carinii. These data, although preliminary, indicates that the addition of Rituximab to auto-transplantation leads to decrease in immmunoglobulin and neutrophil levels after transplantation.
Assessment of the Aryl Hydrocarbon Receptor Gene as a Therapeutic Target in Childhood T-Lineage Acute Lymphoblastic Leukemia.
Authors: Meier Marrit , den Boer Monique L. , Broekhuis Mathilde J.C. , Stam Ronald W. , van Wering Elisabeth R. , Janka-Schaub Gritta E. , Pieters Rob 
Published: April 2020

Abstract
T-lineage ALL is an unfavorable subtype of childhood ALL and is associated with in-vitro resistance to drugs. Therefore the identification of novel genes that may serve as targets to modulate drug resistance is desirable. We compared the gene expression profile of 28 pediatric T-ALL patients being either sensitive (DNRS) or resistant (DNRR) to daunorubicin. The aryl hydrocarbon receptor (AHR) gene appeared to be highly discriminating between DNRS and DNRR T-ALL patients. AHR is known to mediate signal transduction in response to xenobiotics by activating the transcription of xenobiotic-responsive genes such as CYP1A1 and CYP1A2. Expression analysis by real-time quantitative PCR confirmed that basal AHR mRNA levels in ALL cells derived from patients is correlated with DNR resistance (Rs=0.41, P=0.02). Exposure to DNR of the REH cell line expressing a low AHR level led to a 40-fold induction of AHR mRNA. In two other cell lines (i.e. HL60 and SEMK-2) expressing high levels of AHR the upregulation was only 1.4-fold. In REH, the 40-fold induction of AHR after DNR exposure was inhibited by 40% after pre-exposure to the AHR inhibitors salicylamide (SAL) and geldanamycin (GA). Pre-incubation of leukemic cells of T-ALL patients with SAL or GA prior to DNR exposure had a synergistic effect on DNR sensitivity. In addition, transfection of SEMK-2 cells with AHR-specific siRNA resulted in the reduction of AHR expression by 80% after 24 h and had also a synergistic effect on DNR induced cell kill up to 96 hours after siRNA treatment. We conclude that a high expression of the AHR gene is involved in DNR resistance in childhood T-ALL and that AHR may serve as a very attractive new therapeutic target.
Distribution of CMV Glycoprotein B Genotypes after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single Center Study.
Authors: Wu Xiaojin , Wu De Pei , Ma Xiao , Sun Aining , Chang Huirong 
Published: April 2020

Abstract
Objective: To study the distribution of CMV glycoprotein B (gB) genotypes in the patients with CMV infection after allo-HSCT
Methods: Seventy-four patients undergoing allo-HSCT were enrolled in this study. After allo-HSCT, all the patients were detected for CMV gB DNA in peripheral blood by haplo-nested PCR methods;The CMV gB DNA positive samples were screened, which were sufficient for enzyme digestion. Glycoprotein B typing was performed through digesting PCR products with RsaIand HinfI;The sequences were mensurated with ABI PRISM 377 XL DNA Sequencer.
Results: The PCR products of thirty-eight patients were digested with enzyme. the distribution of gB genotypes was as follows:I(gB1) 19/38 (50.0%), II(gB2) 3/38 (7.89%),III(gB3) 14/38 (36.84%), and unclassification 2/38 (5.27%).
Conclusion: The distribution of gB genotypes was different in the patients with CMV infection after allo-HSCT; There may be exiting new genotype.
Gene Expression in Leukemic Blasts Persisting at Day 8 of Induction Therapy in Childhood ALL Displays a Common Shift towards Terminally Differentiated B Cells and a Cytoreduction-Associated Impairment of the Translational Machinery.
Authors: Rhein Peter , Scheid Stefanie , Ratei Richard , Hagemeier Christian , Seeger Karl , Kirschner-Schwabe Renate , Schrappe Martin , Spang Rainer , Ludwig Wolf-Dieter , Karawajew Leonid 
Published: April 2020

Abstract
In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. To approach the mechanisms of therapy resistance, we addressed genome-wide gene expression in blasts persisting after one week of induction therapy (day 8 blasts) and their molecular signatures as compared with blast cells at initial diagnosis (day 0 blasts). In order to approach this issue experimentally, a procedure has been established including flow sorting of leukemic blasts by their leukemia-associated immunophenotype and preparation of cRNA, starting from a small number of cells. Blast cells from 12 patients with precursor B-cell ALL were investigated using Affymetrix HG U133A microarrays, and genes commonly up- or down-regulated in blast cells under therapy were identified in matched pairs of day 8 and day 0 samples. In spite of the heterogeneous clinical features of the patients (mean rate of cytoreduction after 7 days of initial therapy = 82%, range between 33% and 99%), we were able to determine a set of 310 genes whose expression was commonly changed between day 8 and day 0 with an estimated false discovery rate of 0.05. The identified set of genes indicated inhibited cell cycling, reduced metabolism, and expression changes of multiple factors related to B-cell differentiation. These changes collectively suggested that gene expression in day 8 blasts is shifted towards resting mature B cells. To test this hypothesis, we isolated normal B cells from peripheral blood samples of leukemic patients and compared their gene expression to that of leukemic blasts using Principal Component Analysis (PCA). PCA revealed that day 8 samples are positioned between day 0 samples and normal B-cell samples, and statistical significance of this observation could be established using the Jonckheere-Terpstra test. Changes of B-cell differentiation markers on protein level supported this finding. In addition, we analyzed all genes with regard to the correlation of their expression changes with the rates of cytoreduction in peripheral blood. We observed differential impairment of the key components of the translational machinery including ribosome, eukaryotic 43S preinitiation complex and eukaryotic 48S initiation complex. Overall, expression levels of these factors decreased in therapy-sensitive patients but did not change in therapy-resistant patients. Taken together, investigation of leukemia cells persisting during therapy identifies common and individual expression changes which may potentially affect sensitivity towards anti-leukemic agents and offers new insights into the mechanisms of therapy resistance in ALL.
Iron Overload as a Potential Predictor for Short Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia.
Authors: Park Sun Young , Kim Jin Seok , Kim Yuri , Park In Hae , Chun Hyun Ju , Cheong June-Won , Min Yoo-Hong 
Published: April 2020

Abstract
Iron overload is associated with free radical generation and associated with an increase in toxic deaths after hematopoietic stem cell transplantation (HSCT). To evaluate pre-HSCT iron status influencing outcome and incidence of long-term complications, we analyzed 48 adult patients who underwent allogeneic HSCT for acute leukemia in the first complete remission (CR) status. We measured the iron status including serum iron, total iron binding capacity and serum ferritin in patients immediately before allogeneic HSCT. We defined iron overload prior to the HSCT as serum ferritin level ≥ 3000μg/L or transferrin saturation (TS) ≥ 100%. Seven (14.6%) cases were included in the iron overload group; five cases with ferritin level ≥ 3000 μg/L, two cases with TS ≥ 100%. Twenty-nine were the patients with acute myeloid leukemia (AML) and 19 were acute lymphoblastic leukemia (ALL). Thirty-five patients received the myeloablative conditioning regimen and 13 the reduced-intensity transplantation (NST). There were no significant differences in the rate of marrow engraftment and graft failure in relation to iron overload. The incidence of acute graft versus host disease (GVHD) and chronic GVHD in the iron overload group (14.3% and 42.8%, respectively) was not different compared to that in the non-overload group (46.3% and 34.1%, respectively). We analyzed the association between the iron overload and transplantation-related complications. There was no significant difference in the incidence of transplantation-related mortality and venocclusive disease between the two groups. The relapse rate after HSCT was higher in the iron overload group compared to control group (57.1% and 22.0%, respectively), although the statistical difference was not observed. The disease-free survival (DFS) rate at 24 months was significantly lower in the iron overload group (42.9%) compared to the non-overload group (65.6%, log rank test, P = 0.034). In conclusion, iron overload is considered to be one of the poor prognostic variables valid in the allogeneic HSCT settings. Iron chelation therapy before HSCT can be suggested for improving transplantation outcome.
Single Agent Gemtuzumab Ozogamicin (Mylotarg) Can Induce Hematologic Remissions in Patients with Refractory Acute Myelogenous Leukemia (AML) Relapse Following Allogeneic Stem Cell Transplantation but May Precipitate Acute Graft-Versus-Host Disease (GVHD).
Authors: Agha Mounzer E. , Raptis Anastasios , Miller Sarah B. , Taylor Michelle , Mapara Markus Y. 
Published: April 2020

Abstract
Relapse following allogeneic transplantation in the absence of GVHD is usually treated by withdrawing immunosuppressive therapy followed by donor lymphocytes infusions for the induction Graft-versus-Leukemia (GVL) effects. However, if this fails to result in graft-vs-leukemia effects, the prognosis for such patients is usually very poor. Re-induction therapy seldom has an effect on such patients, and the morbidity from full induction is substantial.
Patients: We retrospectively studied five patients with AML, who relapsed following allogeneic stem cell transplantation (SCT). Three patients had their transplant from HLA-identical siblings, and two from matched unrelated donors (URD). Both patients with URD transplant had a one HLA class I antigen mismatch.
Treatment Plan: After withdrawing the immunosuppressive therapy, no signs of GVHD was noted in any of the patients. All patients were then treated with Mylotarg 9 mg/M2 on days 1 and 14. All five patients received both doses. Three patients did not respond and died of progressive leukemia. Two patients achieved complete remission as documented by BM biopsy. One patient who had a one antigen mismatch URD SCT and who had evidence of skin and liver GVHD prior to the relapse, remains in remission without any evidence of GVHD, and off immunosuppressive therapy (day +327 post-BMT). The second patient, who never had GVHD prior to relapse, developed aGVHD of the skin and liver one months after Mylotarg therapy. Despite intensive immunosuppressive therapy, he continued with progressive GVHD of the skin and liver died of GVHD on day +224 post-SCT with no signs of recurrent leukemia.
Conclusions: Gemtuzumab Ozogamicin is effective in inducing hematologic remissions in refractory AML patients who relapse following allogeneic SCT. Mylotarg may precipitate aGVHD and we hypothesize that secondary inflammatory reactions following the cytolytic effects of the immunotoxin may be involved in the induction of GVHD. Caution should be exercised if this treatment is to be combined with donor lymphocyte infusions. Prospective studies are warranted to evaluate the role of Mylotarg in treatment patients in relapse following allo-HSCT and its effect on precipitating GVHD.